November 23, 2020

Route for arthritis and heart failure therapy through vagal nerve stimulation

A new paper provides timely evidence to explain the therapeutic benefits of vagal nerve stimulation (VNS), a nervous system-modifying treatment that proponents say could offer relief to patients with lupus, arthritis and even heart failure.

It’s a prospect that sounds too good to be true. One 20-minute outpatient surgery could lead to relief from epilepsy, depression, arthritis, heart failure and lupus. That’s the ultimate promise of VNSn, a technique that has accrued interest from enthusiastic startups and major biopharma firms alike.

Importantly, it has also accrued some convincing evidence to back up at least some of its claims – VNS has been approved by the FDA as a therapy for treatment-resistant depression and epilepsy. As of 2015, 100,000 people worldwide had received a VNS implant.

But large gaps remain in our understanding of how VNS works. One of those gaps has now been plugged with the publication of a paper investigating how a technique called anodal block works to allow targeted stimulation during VNS. The research team behind the paper, led by Dr Stavros Zanos, have published their work in Scientific Reports.

What is vagus nerve stimulation?

VNS involves implanting electrodes on the vagal nerve near the carotid artery in the neck. The vagal nerve is in charge of routing signals between the brain and the peripheral organs. As Zanos, an assistant professor in the Institute of Bioelectronic Medicine at the Feinstein Institutes for Medical Research, explains, this means it is a uniquely attractive target for neurotechnology. “This is primarily the nerve that the brain uses to convey information to the organs and change the way they function. And also, it’s the main nerve through which information about the function of the organs is conveyed back into the brain. Because it’s such an important nerve for ongoing physiology, it’s a very attractive target for neuromodulation,” says Zanos.

During VNS implantation, a pair of electrodes is attached to the vagus nerve. Depending on the electrode polarity, signals to or from the brain are stimulated or blocked when the VNS device is activated. 

But the nervous system is a little more complicated than a two-lane highway. Nerve fibers sending signals in different directions exist within these larger bundles. Getting the level of stimulation right to ensure therapeutic benefit is of central importance, but is currently done quite crudely, Zanos tells me: “The way VNS is done clinically is by increasing intensity. The healthcare provider changes some parameters, most notably the intensity, until the patient starts getting some side effects. Typically, those side effects have to do with contraction of the laryngeal muscles, so it causes coughing, and voice hoarseness.”

This is far from optimal, and Zanos says that fine-tuning the approach is a priority. “If we wanted to deliver an individualized therapy, we would have to know exactly how we’re affecting the physiology of a specific individual,” he says.

A biomarker for anodal block?

Anodal block is a central tenet of the current surgical procedure. The precise placement of the VNS electrodes can limit nerve conduction in the fibers under the positively charged anode – back in the simplified highway example, this is the equivalent of setting up a tollbooth for traffic going in one direction – the flow is slowed, if not stopped. But evidence that anodal block works this way in practice was sorely lacking from the wider literature. Would it be possible to find a biomarker, Zanos wondered, that could show that anodal block works as intended?

Zanos and his team investigated this possibility by carrying out experiments with rats. Firstly, they needed to see what would happen when electrical impulses up and down the vagus highway were stopped entirely. The rodents had VNS devices implanted, and then had their vagus nerve cut either above or below the implant – completely ending any vagus electrical stimulation towards the brain or the peripheral organs, respectively.

Zanos’ team noticed a consistent marker. Rats with intact vagus nerves showed a heavy reduction in their breathing and heart rates. When the same rats had their vagus nerve severed near the brain, the rats’ breathing rates returned to normal whilst the heart rate remained low. Severing the nerve nearer to the body had the opposite effect.

This told Zanos’ team that:

  • VNS device signaling towards the brain reduces breathing rate
  • VNS device signaling away from the brain reduces heart rate

With these easy-to-measure markers identified, the next step was to work out whether breathing and heart rate were consistently affected by anodal block.

The theories behind anodal block suggested that if the anode polarity was towards the brain, then the VNS device’s effects on breathing rate would be reduced. Anode polarity facing the body would impair the effects on heart rate.

Whilst the same drastic changes seen in the first experiment were not present – the rats in this group had intact vagus nerves, so signals still traveled both ways – Zanos noted that their results supported the theories around anode block in a large number of the rats studied.

Importantly, these results weren’t consistent across all the rats studied. Three rats actually showed reversed effects. This paradox, says Zanos, is likely to be explained by the stimulation of the nearby aortic depressor nerve by the VNS. This unintended stimulation hasn’t proved an issue in human VNS studies, so is likely to be a quirk only seen in certain rodents.

Even if the inconsistent data has an explanation, the study still highlights that the mechanisms behind VNS would be much easier to understand if those individual types of nerve fiber could be better identified. Zanos says this will be the target of an upcoming paper that should advance understanding in the area further. In the upcoming paper, says Stavros, “We look at even finer relationships between some of these biomarkers; heart rate, breathing rate, but also additional biomarkers with the activation of specific fiber types.”

Zanos suggests his team’s data supports the idea that anodal block can make VNS more directional and targeted. But there is obviously more research to be done to support our understanding of why VNS works. This, says Zanos, could lead to the technique meeting its potential sooner than we might think. He highlights two US-based companies, LivaNova and Set Point Medical, who are investigating VNS for heart failure and rheumatoid arthritis respectively. “My guess is that in the next two or three years at least one of these [companies], based on what I what I see in preliminary reports, will be successful, and VNS will be part of the therapeutic options for physicians for these two diseases.”

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