In the immediate aftermath of a stroke, time is of the essence. Doctors need to restore blood supply to the affected brain area as quickly as possible—or else, starved of oxygen, millions of neurons and supporting cells will quickly die off, leading to paralysis, sensory loss or worse.
A new neurostimulation device could help. By electrically tickling a cluster of nerve cells located just behind the nose, the Ischemic Stroke System (ISS500 for short) is designed to promote the release of neurotransmitters and other signaling molecules that enhance blood circulation to the brain.
More blood flow means less cell death—which ultimately should lead to improved muscle strength, walking ability, and other motor functions.
Yet, experts remain divided on whether BrainsGate, the Israeli company behind the device, has definitively shown that the ISS500 system works as intended.
On December 10, an advisory panel to the US Food and Drug Administration (FDA) voted unanimously that the device was safe. But the committee members split on whether efficacy had been adequately demonstrated in clinical trials.
“It does look like there’s a biological effect here at a safe level,” says Michael Hill, a stroke specialist at the University of Calgary in Canada, who consults for BrainsGate. “It is pretty interesting technology.”
But whether the existing body of data is enough BrainsGate to win approval is unclear. “They might just need another bit of evidence to get it across the finish line,” Hill says.
Citing concerns about study design, seven of the panel’s 13 members insisted that another trial was needed to confirm the device’s benefit. But others, noting that the regulatory bar for approval is typically lower for devices than drugs, either gave the ISS500 their blessing or abstained from making a final determination.
The FDA is not required to follow its panels’ recommendations, but usually does. European regulators endorsed the device last year, but BrainsGate has been waiting for a U.S. decision before beginning any sort of wide-scale commercial rollout.
Jeffrey Saver, a vascular neurologist at the UCLA Stroke Center who co-led clinical testing of the device and serves as a scientific advisor to BrainsGate, is hoping for a favorable FDA ruling. “This is not a me-too device,” he says. “This is a whole new way of taking care of patients.”
As it stands, patients who suffer from ‘ischemic’ strokes—the most common kind, caused by blocked arteries to the brain—have two main treatment options. They can take clot-busting drugs to clear the obstruction, or have tiny tubes snaked into their blood vessels to physically remove the offending junk.
But around 10 to 15 percent of patients are not eligible for these interventions. The drug treatment must be started in a short time window after stroke onset, and a heightened chance of brain bleeds can make the clot-busting therapy too risky for some individuals. Meanwhile, some people have twisted and tangled networks of blood vessels, and this maze-like architecture can be impossible to navigate them with any sort of catheter-guided device.
The ISS500, if approved, would offer a treatment alternative for those stroke-afflicted individuals who currently have no other options.
The neurostimulator is built around a toothpick-sized device comprised of a bipolar electrode on one end, an electronic circuit board on the other, and a bendy connector piece in between. “The biggest engineering challenge was to minimize everything and make the implant strong on the one hand and flexible on the other,” says BrainGate’s Eyal Shai, vice-president of stroke efforts at the company.
Doctors use an image-guided procedure — informed by CT scans, dental impressions, a stereoscopic camera, and optical tracking software — to inject the device through the upper palate of the mouth into just the right spot next to the target collection of nerves, the sphenopalatine ganglion (SPG). A hockey puck–shaped transmitter placed over the cheek then wirelessly transmits energy to the implant via magnetic inductance.
This rendering shows the puck-shaped transmitter that supplies power to the ISS500 after it has been implanted.BrainsGate
More than 30 years ago, pioneering research teams led by the Australian neurologist Peter Goadsby and the Swedish neurophysiologist Lars Edvinsson first showed that electrically stimulating the SPG could boost blood flow to the brains of rats and cats.
But back then, “the idea that nerves would change brain blood blow was disruptive,” says Goadsby, now at King’s College London and UCLA. The brain’s metabolic activities—not electrical wiring—were thought to drive cerebral blood circulation. Goadsby and Edvinsson, like most others in the field, moved on to study more direct connections between the SPG and nerve signaling linked to headache pain.
Two years ago, for example, Goadsby led a trial showing that high frequency, on-demand stimulation of the nerve bundle, using a remote control activated device implanted through the upper gums, helped bring pain relief to people prone to cluster headache attacks. But the company behind that device, Autonomic Technologies, went out of business in 2018 — and it could be several years more before the platform’s new owner, a startup called Realeve, manages to bring that type of SPG neurostimulator to market.
In principle, the ISS500 system could be adapted for headache treatment. It could also help with getting drugs into the brain, as BrainsGate cofounder David Yarnitsky, a neurophysiologist at the Rambam Medical Center in Northern Israel, demonstrated in proof-of-concept experiments with rats and dogs in the mid-2000s.
Yet BrainGate has long prioritized stroke recovery. And by gently stimulating the SPG in just the right way—rather than overexciting the nerve bundle, as one might do to block the headache pain pathway—the company has honed its technique for augmenting blood flow to the brain and restoring neurologic function.
Clinical testing with the ISS500 system started in 2006. A small feasibility trial demonstrated the device’s potential in post-stroke care. A pair of randomized, sham-controlled trials followed, collectively showing that SPG stimulation works best in people with strokes that affect the cerebral cortex (rather than some other brain structure located deeper inside the head).
In those patients, daily 4-hour sessions with the ISS500 system, commenced within 24 hours of an ischemic attack and administered over five consecutive days, markedly reduced disability and improved quality-of-life metrics compared to sham treatment.
Responses were especially pronounced when doctors administered the therapy at low- to mid-range intensities—the stimulation sweet spot. Hand strength increased. Some people who had lost the ability to understand or express speech began speaking again soon after the neurostimulation.
But BrainsGate did not initially position its device as a treatment exclusively for strokes of the cerebral cortex. The importance of stroke location was only noted part way through the company’s clinical development program. And it was well into a 1,000-person, pivotal trial—but before anyone knew results of the trial—that BrainsGate decided to amend its analysis plan and introduce a critical test of device efficacy based on outcomes only among participants with cortical strokes.
In the end, the device showed little benefit across the study population as a whole. It only produced meaningful improvements in disability measures in the subgroup with strokes of the cerebral cortex.
That analytical switcheroo irked some outside observers—hence the decision of many FDA advisors to recommend against authorization for the time being. In their opinion, BrainsGate needs to conduct a better-designed confirmatory trial.
It’s now up to agency staffers to determine whether such a trial is necessary. A decision is expected by February.
If approved, the ISS500 system would become the second implantable device authorized for treating stroke in less than a year. Back in August, the FDA approved the MicroTransponder Vivistim system, which delivers mild electrical pulses to the vagus nerve in the neck and has been shown to assist with long-term stroke recovery when paired with physical therapy.
Other complementary devices could soon follow. Wearable caps that deliver magnetic or direct current stimulation to precise points in the brain are being trialled in stroke clinics. And according to Realeve CEO Jon Snyder, his company is planning to test its investigational SPG neurostimulator as a rehabilitation aid for stroke as well.
Saver, the UCLA neurologist, welcomes the arrival of these various nerve-stimulating treatment options. As he points out: “Stroke neurology first had a pharmacologic age. Then it had an endovascular device age. And I think we’re now beginning the age of a third set of modalities—with neuromodulation.”