đ§ Hacking the nervous system to reduce inflammation
How the vagus nerve could transform the treatment of inflammatory conditions
Today weâre talking bioelectronic medicine. Also known as neuromodulation, or biostimulation, or electroceuticalsâŠ
Whichever name you pick, itâs an emerging field that explores the use of precise electrical pulses to treat chronic diseases.
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Alright, letâs dive inâŠ
đ€·ââïž Problem
Autoimmune diseases like rheumatoid arthritis (RA) affect 5-7% of the population. 1.5M people in the United States have RA and it is 3x more common in women.
Treatments include steroids, disease modifying agents, and monoclonal antibodies, all of which can have significant side-effects.
There is a growing consensus that chronic inflammation plays a role in causing and advancing autoimmune diseases like RA.
đĄ Solution
Use implantable devices to target the nerves that modulate the immune system in order to reduce inflammation and the long term impact of inflammatory conditions.
đ Terms
We donât want to weigh you down with jargon, but understanding how the nervous and immune systems are linked requires some baseline knowledge. Buckle up for a crash course in neurology and immunologyâŠ
Vagus nerve. The transatlantic cable of the human body. Originating in the brain, it has a big role in the autonomic nervous system (ANS) and helps control the heart, lungs and digestive tract (amongst other things).
The inflammatory reflex. Mediated by the vagus nerve, this is the bodyâs innate autonomic reflex that detects and responds to the production of pro-inflammatory mediators in order to restore balance to the immune system.
Tumour necrosis factor (TNF). One of many inflammatory molecules produced by cells of the immune system. TNF levels can be high in conditions like RA. Many of the drugs used in autoimmune conditions block TNF or its receptor. Electrical activity in the vagus nerve is the start of a cascade that can limit the release of TNF.
Vagus nerve stimulation (VNS). A medical treatment that involves delivering electrical impulses to the vagus nerve, usually via an implanted device in order to modulate downstream effects.
đŒ Use cases
Modulating the bodyâs neural networks sounds like some futuristic tech, but its already being used to treat drug-resistant epilepsy and depression. Letâs take a look at some of the more emerging use-cases for bioelectronic medicine:
***Trigger warning for those who hate small sample sizes and non-randomised techniques***
Rheumatoid arthritis (see âImpactâ below)
Crohnâs disease. A 12 month pilot study in 9 patients with Crohnâs disease found reduced gut inflammation following VNS therapy.
Alzheimerâs disease (AD). Swedish researchers followed up for 17 AD patients for one year who were treated with VNS and found their scores on cognitive tests were maintained or even improved.
Septic shock. Check out this patent for a method to inhibit the release of pro-inflammatory mediators, particularly those implicated in septic shock.
đ History
The history of VNS is an illustrative example of how âoff-targetâ benefits from a novel intervention can lead to advances in other fields. Whatâs even more surprising however, is just how far back this technology goes.
We start in 19th century AmericaâŠ
1880. American neurologist (and moustache aficionado) James Corning uses VNS to treat epilepsy, believing seizures were due to changes in cerebral blood flow. Side effects are common and his approach doesnât really catch on. Bummer.
1988. A whole century later, Cyberonics PLC (now LivaNova) develop a neurocybernetic prosthesis (a name that unfortunately didnât catch on) to reduce the frequency and severity of epileptic seizures. Another renowned American neurologist J Kiffen Penry is the first to implant the device clinically.
1997. By now, the evidence has accrued, and both the FDA and European regulator approve the use of VNS for medication resistant epilepsy. Researchers notice however that the epilepsy patients treated with VNS show improved moodâŠ
2000. A pilot study of mood in epilepsy patients treated with VNS shows significant improvements in mood independent of seizure control - suggesting VNS has a distinct and separate effect on depressive symptoms. Saaaaaaaay whaaaaat?
2002. Neurosurgeon Kevin Tracey (see TED Talk link below), publishes a paper in Nature titled âThe Inflammatory Reflexâ. In it he explores the interface between the nervous and immune systems and suggests there is an opportunity to treat inflammation through âhard-wired neural systemsâ.
2005. Following further trials, the FDA approves VNS for the treatment of patients with chronic or recurrent depression that has failed to respond to conventional treatments.
2010s. An increasing body of research shows promising results for neurostimulation in animal models of inflammatory disease and subsequently in humans with RA. This kickstarts a concerted effort to bring novel medical devices to market for inflammatory conditions.
đ„Â Players
The bioelectronic device market is expected to reach an annual market cap between $16B and $60B within the next 5 to 10 years. Here are some of the firms focusing on devices that target the vagus nerve:
LivaNova. The âOGâ VNS player. They provide the âSYMMETRYâ VNS therapy system for treatment-resistant depression and âVNSTherapyâ for drug-resistant epilepsy. Currently recruiting for the âRECOVERâ study which will further evaluate the benefit SYMMETRY has on depression.
Inmedix. Produce the ANS Neuroscan, a device pending FDA approval that can evaluate vagus nerve activity by investigating heart rate variability (HRV). The aim is to assess which patients will benefit most from neuromodulation of their vagus nerve.
Feinstein Institutes for Medical Research. Recently developed a long-term implant model for VNS stimulation (in mice). The device should enable more thorough and long-term preclinical VNS research.
The Bioelectronics Laboratory. Part of the Feinstein Institute. They partner with labs to perform preclinical and clinical research to develop new therapies in bioelectronic medicine.
Setpoint Medical. A bioelectronic medicine company which has developed a platform comprising an implantable microregulator, wireless charging collar and an app. Itâs currently an investigational device undergoing clinical evaluation but the company is sponsoring the RESET-RA study to help build the evidence base.
Galvani Bioelectronics. A joint venture between GSK and Verily Life Sciences, Galvani develops bioelectronic medicines to treat chronic diseases. Not much to find on their website about current devices or treatment they are developingâŠ
đ Impact
A randomised study of 14 participants with severe RA (funded by Setpoint Medical) found that an implanted neurostimulator was safe, well tolerated and reduced the signs and symptoms of the disease.
Of course, itâs a tiny study, but it supports the progression to larger randomised trials.
đ€ Challenges
Side-effects. Itâs no surprise that having a device inserted in your neck isnât without its risks. Some relate to the proximity of the vagus nerve in the neck to another nerve that controls the vocal cords. Difficulty swallowing, a hoarse voice and even vocal cord paralysis can arise from the procedure.
Invasive. The insertion of neuromodulatory devices requires a minor operation, normally at the hands of a specialist vascular or neurosurgeon. Careful consideration is required to determine if the benefits of the device outweigh the risk of the procedure for any given patient.
Cost. Complex implantable devices, a surgical procedure, wireless charging. bioelectronic based treatments arenât cheap - which raises questions around funding. That being said, biologics used to treat conditions like RA are also expensive - costing around $20K per patient, per year. Bioelectronics might have more upfront costs but could be cheaper in the long term.
Complex systems. Fine-tuning bioelectronic treatments requires greater understanding of neural circuitry at the systems level. Computing power has allowed us to understand the electrical activity of 100s maybe 1000s of neurons. But weâre still a long way off from understanding pathways involving 100 million (the gut) or 100 billion (the brain).
đ Opportunities
Precision. Itâs not just about zapping the vagus nerve periodically. Improvements in medical devices allow researchers to zero-in on specific nerve fibres and adjust the amplitude and frequency of electrical pulses to reduce side-effects.
Proximity. Researchers are exploring ways in which the vagus nerve can be stimulated closer to its intended target in order to reduce side effects. Most VNS systems are inserted near the neck, but if the gut is the intended beneficiary, future devices could be inserted there to reduce off-target effects.
Non-invasive. Researchers have explored the effect of non-invasive stimulation of the vagus nerve around the ear in order to reduce pain and fatigue in systemic lupus erythematosus (SLE). The study involved only a few patients but the results were promising.
New nerves. Itâs not all about the vagus nerve. Obstructive sleep apnoea can be treated using an implanted device that stimulates the nerve which controls the tongue. Thereâs no immune angle here but neuromodulation in general could have a wide reach.
Closed loop. Current VNS or bioelectronic treatments are based around regular stimulation of the nerve in question one or more times a day. Eventually, a device might be able to listen in on nerve activity and decide on how to respond in real-time without external control.
Self-powered. Powering tiny devices, particularly those that might be inserted into deep tissues, is difficult. Advances in piezoelectric devices (which generate electric charge from mechanical stress) could facilitate ultra-small devices without charging or large battery requirements.
đź Predictions
Miniatures. Advances in microchips, power storage and wireless charging will make implantable bioelectronic devices easier to insert and use. Current devices are about the size of a pill. Expect them to get smaller still.
Inject, donât cut. As devices get smaller, they will eventually be injectable, avoiding the requirement for surgery and cutting out (no pun intended) some of the regulatory hurdles. (Itâs easier to get approval for something that doesnât require a surgical operation).
Mainstream. Within the next decade, neuromodulation will be a mainstream treatment for one or more inflammatory and autoimmune conditions. Early human trials are promising. Large randomised trials are required to convince the wider medical community.
Complementary. Donât throw out the monoclonal antibodies or steroids just yet. Bioelectronic approaches will probably be used alongside existing treatments, hopefully at lower doses where drug side-effects are less likely.
Patient acceptance. Pharmaceutical treatment for conditions like RA can be life changing, but the side-effects are often grim. Bioelectronic approaches will lead to higher patient satisfaction and improved quality of life.
đ Links
This TEDMED talk by Kevin Tracey, neurosurgeon and CEO of the Feinstein Institute, talking about how nerves can modulate the immune system.
This article on the rise of bioelectric medicine
Thatâs it for this week - catch ya next time đ