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As explored in our previous blog The Neuromodulation Landscape, neuromodulation and bioelectronic medicine are already benefitting patients around the world for a variety of afflictions and illnesses. They are also new fields set to explode in growth over the next few years, as the industry steps away from a ‘one size fits all’ view on chronic disease therapies. The focus now becoming more honed onto personalised medicine. However, that’s not to say that there aren’t a few things that can’t be learned from traditional pharmaceutical therapies. Here, we’ll explore a few pharmacological concepts that scientists suggest could be considered for translation into the neuromodulation process.

From pharmacology to bioelectronic medicine

The body has three main control axes: signal (leveraged by small molecules), the immune and neural.

Image of a female doctor giving good news to an elderly male patient.

So far, pharmaceutical companies have been successful in tapping into the signal and immune controls, creating pain relief drugs and vaccines that can be used widely by the majority.

However, academia and organisations working in the emerging field of digital therapies and bioelectronics such as BIOS Health, are working towards a future where healthcare will offer a more personalised approach; where precision-driven treatments leverage the nervous system to benefit individual patients (read our blog The Next Frontier In Medicine for more information).

Examples of neural activation and inhibition

The effect a drug can have on the body can either ‘activate’ an internal process or ‘inhibit’ it. Examples of this would be angina medication which causes cardiac stimulation and enlarges blood vessels to allow better blood flow. As opposed to beta-blockers which reduce arterial blood pressure by reducing cardiac output.

Neuromodulation works in a similar way to either ‘stimulate’ or ‘block’ specific nerves. In many studies, the vagus nerve is the target. The vagus nerve extends from the brain down the neck and into the chest and abdomen, it controls many significant functions in the body such as respiration and heart rate.

A study on rheumatoid arthritis by Koopman et. al. (2016) suggests that it’s possible to use mechanism-based neuromodulating devices in the therapy of rheumatoid arthritis and possibly other autoimmune and autoinflammatory diseases. This was based on their research which found that by stimulating the vagus nerve (targeting the inflammatory reflex) the production of TNF (tumor necrosis factor, an inflammation-causing protein) was balanced, causing inflammation in the afflicted area to reduce.

Some promise for bioelectronic medicine has also been shown in heart failure by J. Ardell (2017). When a higher intensity of stimulation (or amplitude) was applied to the vagus nerve, the results led to bradycardia (an increased heart rate). While lowering the intensity equalled tachycardia (a decrease in heart rate). This has led to many other studies in this area. Download our whitepaper to find out how BIOS is “Decoding the Neural Control of the Heart” to treat chronic disease.

Addressing the challenges

According to Asad (2019), there have been three randomised human VNS (vagus nerve stimulation) trials to date. But only one of the three reported consistent benefits in the treatment of heart failure. It’s thought that failure may have been due to the stimulation protocols (currents applied, frequency to the nerve etc.) varying in each. So, is it safe to assume then, that stimulation protocols equate to dosing in pharmacology?

A test tube diagram showing the amount of drug in the blood relative to efficacy or toxicity
The Therapeutic Index

If so, then perhaps bioelectronics could also take note of pharmacology’s therapeutic index which refers to drug toxicity in patients. The goal with stimulation (as with dosing in pharmacology) is to deliver the minimal effective stimulation (or dose) while mitigating any side effects. For bioelectronics and neuromodulation, these vary depending on the device used and the disease treated. For example, spinal cord stimulation (SCS) could cause headaches and cramps, whereas common side effects of VNS include apnoea, cough, and gastrointestinal discomfort.

Not all are created equal…

Another point to consider is that stimulation parameters developed in animal models and trials are often directly applied to humans, despite varying anatomy and physiology. N. Stakenborg et. al. (2020) investigated the anatomical structures of nerves in mice, pigs and humans and found that comparatively, they differ greatly in their fibrous tissue and nerve bundle structures. This affects the stimulation thresholds (the minimum intensity required to elicit a response) in the VNS fibres in the different species. Therefore, the study suggests that caution should be employed in translating from one model to another when it comes to neuromodulation therapies scaling-up from animal to human clinical trials. This is underlined by another SPARC study by Musselman et. al (2020) which found that the human stimulation threshold was up to 20 times greater than in rats. Existing drug development scale-up processes could be looked at for clues on how to scale-up neuromodulation therapies. However, scaling-up dose is already a contentious issue in pharmacology as according to Nair (2016), there are four different methods to choose from!

Looking forward: Electrokinetics and electrodynamics Two subdisciplines of study dedicated to ensuring that drugs achieve consistent therapeutic benefits (as well as safety) from one model to another in clinical trial scale-up are PK and PD:

  • Pharmacokinetics (PK) addresses the effect of the body on the drug – including processes such as absorption, drug distribution, and excretion.

  • Pharmacodynamics (PD) is concerned with the biological and physiological effect of the drug on the body.

As our previous blogs have shown, the potential and scope of diseases that could be targeted with bioelectronics and neuromodulation is vast. Particularly for chronic diseases such as heart failure.

And as these fields mature, it may be that we see similar disciplines such as electrokinetics and electrodynamics emerge. Which may investigate the effects of sustained currents over periods of time compared to a staccato application (see the ‘duty cycle’ column in fig.1) or the intensity of frequency.

Table showing the effect of electroceutical stimulation patterns on functional responses
Fig 1. From C. C. Horn, J. L. Ardell, and L. E. Fisher, “Electroceutical targeting of the autonomic nervous system,” Physiology. 2019.

Or perhaps whether the body would continue with the effects of the stimulation long after the treatment has finished. Though still a relatively new field of therapeutics, it’s clear that bioelectronic medicine has a lot of potential as a complementary field of therapeutics to drug development. The nervous system is still vastly untapped, but being linked to so many important functions it cannot be ignored for much longer. And may yet prove to be the next wave in the evolution of personalised/precision medicine.

Missed part two of this series? Catch up here.

  1. Koopman, F. A., Chavan, S. S., Miljko, S., Grazio, S., Sokolovic, S., Schuurman, P. R., Mehta, A. D., Levine, Y. A., Faltys, M., Zitnik, R., Tracey, K. J., & Tak, P. P. (2016). Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. Proceedings of the National Academy of Sciences of the United States of America, 113(29), 8284–8289.

  2. Ardell, J. L., Nier, H., Hammer, M., Southerland, E. M., Ardell, C. L., Beaumont, E., KenKnight, B. H., & Armour, J. A. (2017). Defining the neural fulcrum for chronic vagus nerve stimulation: implications for integrated cardiac control. The Journal of physiology, 595(22), 6887–6903.

  3. Asad, Z. U. A., Stavrakis, S., (2019) Vagus nerve stimulation for the treatment of heart failure. Bioelectronics in Medicine, 2:1, 43-54.

  4. Stakenborg, N., Gomez-Pinilla, P. J., Verlinden, T., Wolthuis, A. M., D'Hoore, A., Farré, R., Herijgers, P., Matteoli, G., & Boeckxstaens, G. E. (2020). Comparison between the cervical and abdominal vagus nerves in mice, pigs, and humans. Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society, 32(9), e13889.

  5. Musselman, E. D., Pelot, N. A., Cariello, J. E. Goldhagen, G. B., Grill, W. M., (2020) SPARC: Biophysical Modeling of Vagus Nerve Stimulation for Translational Scaling of Stimulation Parameters Across Species. The FASEB Journal (34) 1:1.

  6. Horn, C. C., Ardell, J. L., & Fisher, L. E. (2019). Electroceutical Targeting of the Autonomic Nervous System. Physiology (Bethesda, Md.), 34(2), 150–162.

  7. Nair, A. B., & Jacob, S. (2016). A simple practice guide for dose conversion between animals and human. Journal of basic and clinical pharmacy, 7(2), 27–31.

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