Realizing the vision of a new class of medicines based on modulating the electrical signalling patterns of the peripheral nervous system needs a firm research foundation. Here, an interdisciplinary community puts forward a research roadmap for the next 5 years.
With the rapid rise in technology for the precision detection and modulation of electrical signalling patterns in the nervous system, a new class of treatments known as bioelectronic medicines seems within reach1. Specifically, the peripheral nervous system will be at the centre of these advances, as the functions it controls in chronic diseases are extensive and its small number of fibres per nerve renders them more tractable to targeted modulation.
The vision for bioelectronic medicines is one of miniature, implantable devices that can be attached to individual peripheral nerves anywhere in the viscera, extending beyond early clinical examples in hypertension2 and sleep apnoea3. Such devices will be able to decipher and modulate neural signalling patterns, achieving therapeutic effects that are targeted at single functions of specific organs. This precision could be further enhanced through closed-loop control: that is, devices that can record neural electrical activity and physiological parameters, analyse the data in real time and modulate neural signalling accordingly1. For this vision to be realized, a solid research foundation for bioelectronic medicines is needed. This article puts forward a roadmap for the next 5 years towards generating that base.
An emerging community of ‘bioelectricians’
This roadmap has its origins in a meeting of research leaders from academia, industry and government in December 2013, for which neurophysiologists, neural engineers, disease biologists, neurosurgeons, as well as data and material scientists came together to define the research path towards bioelectronic medicines. Three principal research areas crystallized in the meeting: the creation of a visceral nerve atlas; the advancement of neural interfacing technology; and the early establishment of therapeutic feasibility. The direction in these areas has been further synthesized and refined by the authors of this roadmap, with the intention of engaging and expanding an emerging research community interested in bioelectronic medicines. Key elements of the plans in these three areas are summarized here, with detailed points and references provided inSupplementary information S1 (box).
Creation of a visceral nerve atlas
As with the large-scale genome and brain projects (see the NIH interim report for further information), a biological map of structure and function — underpinned by data recording standards and central repositories that enable collaborative data mining — will be crucial. The roadmap focuses on the innervation of visceral organs, such as the lungs, heart, liver, pancreas, kidney, bladder, gastrointestinal tract and lymphoid and reproductive organs. Their specific innervation, including sympathetic, parasympathetic, sensory and enteric systems, needs to be mapped, with the goal of achieving resolution at the level of nerve fibres and action potentials.
Structurally, knowledge of the detailed peripheral nerve wiring will guide the selection of organ-specific points of investigation. The key research steps towards establishing such a structural map are to expand the toolkit for high-resolution tracing and fingerprinting of visceral nerve fibres, establish the intra- and interspecies variation of organ innervation, and then build detailed maps in the most appropriate animal model for each organ. Another important early priority is to advance techniques for imaging the anatomical course and targets of visceral nerves in humans, paving the way for precision implantation of bioelectronic medicines in the clinic.
Functionally, the focus should be on decoding the neural signalling patterns that control individual organs. This approach will hinge on simultaneous recordings of both neural signalling and biomarkers of organ function (for example, blood pressure and cytokine release) that should be mined for correlations, and on stimulation and blocking experiments to test causation. The research should be iterative, drilling deeper into the signals as higher-resolution interfacing technology emerges until the functional units of nerve fibres and their signalling patterns are established.
Advancement of interface technology
Neural interfacing technology provides the basis for mapping neural signals and for bioelectronic medicines. Electrode-based interfaces have long been a work horse in electrophysiology and neuromodulation, but they must be adapted and miniaturized to interrogate visceral nerves effectively: cuff and array electrodes need to be scaled to <100 μm nerve diameter, and new materials and architectures should be pursued that can best address largely unmyelinated nerve structure, irregular neuroanatomy and movement in the viscera. Beyond electrodes, biophysical techniques can both help reveal the complex details of action potential patterns in peripheral nerves and pave the way for less invasive precision neuromodulation in the longer term. Such methods include optogenetic and nanoparticle approaches for deciphering, stimulating and blocking action potentials in a large set of nerve fibres in parallel4, and ultrasonic and tomography techniques for non-invasive recording and modulation.
To capitalize on these advances, we also need to develop platform electronics that control the nerve interfaces and integrate high-bandwidth wireless data transfer, power management and signal processing5. Such platforms need to be made both smaller and more reliable to facilitate long-term recording, stimulation and blocking experiments across animal models. A particular need is to make them compatible with experiments in rodents, for which a wealth of disease models exist — something that was recognized in the innovation challenge singled out by the participants in the December 2013 meeting (see the Innovation Challenge for further information). Miniaturization will also be an important requirement to achieve the broad-reaching clinical application of bioelectronic medicines.
Early establishment of therapeutic feasibility
Therapeutic promise is the real impetus for the research described here. Therefore, a range of proof-of-principle experiments should be initiated. Where successful, these should be followed by optimization of the ‘treatment codes’ — the specific signalling patterns to be introduced in nerves to most effectively treat disease.
Proof of principle here means defining which neural circuits exert influence over disease progression in a representative animal model. By focusing on two types of experiments, rapid read-outs could be achieved across visceral organs and functions: the first is to examine the correlation of neural signals and biomarker patterns during disease progression, and the second is to investigate the effect of blocking and stimulating neural activity during established disease.
A longer experimental phase should then be pursued to determine the treatment code. This testing can be broadly split into four types of investigation. First, the best intervention point on the nerve needs to be established: near to the target organ on small nerve branches or farther from the organ on the larger, mixed preganglionic bundles of nerves. Second, the equivalent to dose–response curves should be developed in the multi-dimensional neural signal pattern space. Third, the potential added benefit of ‘closing the loop’ — self-tuning of the modulation in response to neural patterns and disease biomarkers — needs to be evaluated. Last, the long-term safety of disease-modifying neuromodulation needs to be assessed, including potential immune reactions, neural responses and physiological adaptation. Together, these investigations would lay a solid foundation upon which multiple future bioelectronic medicines could be prototyped.
The research outlined here, and detailed further in Supplementary information S1 (box), aims to serve as a guide for the growing community entering the field of bioelectronic medicines. If executed successfully, it will help bring a new class of precision medicines to patients.