Detecting bladder volume and pressure from sacral nerve signals: the key to future artificial control

Lead Research Organisation: Royal Veterinary College
Department Name: Comparative Biomedical Sciences CBS

Abstract

This project is about the treatment of urinary incontinence, consequent of damage to the spinal cord.

Managing the urinary bladder is of the first importance to clinicians and patients following trauma to the spinal cord. Historically, kidney damage due to high bladder pressures and/or infection was the usual cause of death resulting from such an injury. Infections still raise mortality and morbidity, exacerbated by the risk of antibiotic resistance. In order to achieve urination-i.e. complete voluntary micturition (CVM) and as an alternative to the expensive process of intermittent sterile catheterisation, a neuroprosthesis for controlling the bladder after spinal cord injury (SCI) was developed by GS Brindley at the MRC Neurological Prostheses Unit in London 30 years ago. The Brindley method employs sacral anterior root stimulation (SARS) but is not popular in Europe, in terms of the fraction of the SCI population treated, because implantation of the device is accompanied by cutting the sacral posterior (sensory) nerve roots (rhizotomy) to prevent reflex incontinence during bladder filling and improve stimulated voiding. Clearly there is a need for a new neuroprosthesis that is more widely acceptable (primarily because no rhizotomy is necessary) and which, in addition, reduces the lifetime cost of care. The aim of this project is to design and demonstrate such a device.

Since its introduction, the Brindley method has been improved in several ways in attempts to address the problems mentioned. However, in spite of these developments, at present (a) no satisfactory, practical method exists for detecting the onset of bladder contractions in a chronic implant and, (b) no method is available to inform the patient of the level of bladder fullness to indicate when the bladder should be emptied. These are critical obstacles to the design of a complete prosthesis and our proposed solution is to use the bladder neural signals themselves since surgically implanted electrodes are essential anyway (i.e. for stimulation). A suitable site for the electrodes is the extradural roots; this is surgically attractive and electrodes are routinely implanted here in the Brindley procedure. In order that the nerves are similar to those in man, it is essential to use a large experimental animal as a preclinical model and we propose to use sheep for these experiments.

Publications

10 25 50
 
Description In the first part of the grant, we have designed a new nerve implant (called 'neuroprosthesis') created to be placed around sacral nerves; these nerves naturally control the urinary bladder. Our aim is to create an intelligent implant to control incontinence problems in people after severe spinal cord injury. This implant was designed based on the sheep anatomy and the size of their nerves and it is hoped that an identical implant could be used in human. The design of the neuroprosthesis was done so that it could ensheath the nerve and record nerve signals with adequate impedance, i.e. to avoid the background noise of the environment. The electrode design is a cuff containing an array of electrodes (multi-electrode cuff). Once satisfied with the design, we have then tested it's ability to record nerve signal when experimentally triggered along the nerve. We could successfully prove that the new implant was able to detect electrically induced nerve signals. In particular, the implant could record speed of nerve signals as they travelled through the implant. But importnatly, we could also detect signal from skin stimulation (i.e. sensory skin signals); we also recorded signals signals from the bladder but these are not discernable yet from background noise and further analysis is required. The processing of the recordings is our next step.
Exploitation Route We have presented the design of our implant at a conference and we will make this available through publication. This implant can be exploited by others for further testing in view of recording sensory signals from nerves. In the particular expample of incontinence, we engage with sacral nerves and hope to record bladder sensory signals such as bladder fullness. Having now progressed the design of our implants, other might be able to use it in this indication. However, it is possible that other researchers will use it to record sensory signals from other nerves, such as the laryngeal nerve involved in breathing. Our findings are of interest to the neuroscience communitee, engineers working with implantable materials, and doctors in particular.
Sectors Electronics,Healthcare,Manufacturing, including Industrial Biotechology

 
Description The essence of this project is to investigate if bladder pressure and volume can be estimated using electrodes implanted at an extradural site - sacral nerves - acutely and chronically in a large animal experimental model. The conduction velocities of the sensory (myelinated) afferent fibres from mechanoreceptors of the genital region in sheep are similar to those of fibres conveying bladder pressure and volume information in man (approximately 38 and 41 m/s respectively). In order to discriminate between these signals, we propose to use a method that we have been developing called velocity selective recording (VSR) that may make this possible without using nerve interfaces that are difficult to implant or that endanger these important nerves. The principle of VSR is based on the fact that action potentials (APs) propagate at specific velocities and that these velocities are closely related to the nerve fibre diameter (for myelinated nerves). If, therefore, a recording of neural traffic can be characterised in terms of its velocity spectrum, it will provide a signature relating the recorded signals to their function (VSR can also discriminate between afferent and efferent traffic on a mixed nerve, such as extradural bladder nerves). The method requires multi-electrode cuffs (MECs) and we have used such devices with as many as 11 electrodes along the length of a nerve cuff. Since the signals appearing at the electrodes of an MEC in response to naturally-occurring (physiological) ENG are very small (order of 1 µV) a very low noise environment is required. This requires not only specially-designed recording instrumentation but also an electrically quiet environment with well-characterised and understood background interference sources. This latter requirement is particularly hard to achieve in a modern operating room (OR), which tends to contain many electrically-based devices. Most of our effort to date has therefore been directed towards preparing and characterising the experimental set-up in a designated OR at the Royal Veterinary College (RVC) so that successful neural recordings can be made that make maximum use of our various resources and that do not require expensive additional interference reduction equipment. Initially, we have designed a new nerve interface, multi-electrode cuff (from silicone with steel electrodes), connected to a Cooper cable for signal extraction (photograph 1). The cuff design is based on the anatomy of sheep sacral nerves. Using this implant, we have conducted impedance measurements following stimulation of explanted pig vagal nerves and then live recordings in sheep. This showed impedance values of ~5kO for frequencies ranging 100-1,000Hz, which fulfils theoretical requirements for afferent bladder sacral nerve recording. Then, four acute implantations have been carried out on sheep (15 June 2018, 30 October 2018, 13 December 2018 and 1 March 2019 - photograph 2). The first three experiments were significantly compromised by the presence of electrical interference and only compound action potentials (CAPs) trafficking through sacral nerves, evoked by sacral nerve electrical stimulation were recordable. In response to this, two extra days were spent in the OR (3 January and 1 February 2019) with the instrumentation alone, in an attempt to understand these interfering sources. These efforts were successful and in the most recent critical experiment (1 March 2019) we were able to record physiological ENG in response to touch stimulation of the skin in the region of the animal's tail, innervated by sacral nerves. These recordings were clear above the noise and repeatable. Recording CAPs from both sacral nerve electrical stimulation and skin stimulation validates our new cuff electrode design and brings confidence that the interface nerve / cuff electrode is exploitable. Sacral nerves were sampled in two animals for morphometry to serve as controls against future chronic experiments. During in vivo experiments in sheep, we have acquired new data on sheep's physiological bladder function (during anaesthesia) and found: (i) peak bladder pressures ranging from 23 to 31cmH2O during S2 and S3 electrical stimulation - image 1; (ii) maximal bladder pressure during filling cystometry ranging from 6 to 59cmH2O for infused volumes of 187 to 727mL - image 2; and (iii) a drop in bladder compliance after 4 hours of anaesthesia. So far, we have used two methods for detecting bladder afferent signals: (i) monitoring the running RMS amplitude of the wide-band amplifier output, and (ii) listening to this raw recording during the experiment. Despite filling the bladder to very large volume (1 litre) and the consequent high pressure (up to 59cmH2O), there was no apparent neural signal. This might be due to the long period of anaesthesia and the observed reduction in bladder compliance, but it shows that signal processing is essential. The challenge now is, therefore, to see whether the bladder afferent signals can be extracted using VSR. In summary, our findings to date have been; 1. A custom 5-channel integrated amplifier system (CMOS asic) has been constructed (configurable for 10 channels as needed) and its performance verified; 2. A new multi-electrode cuff (MEC) has been designed and built (4 electrodes initially but with a capability to increase to 10 or more); 3. A special tool has been designed to aid the implantation of the MECs on extradural roots of sheep; 4. The OR has been characterised for electrical interference and counter measures taken so that the recording instrumentation is not compromised by the environment; 5. The cuff impedances (2-and 4-wire configurations) have been extensively characterised in vitro and in vivo; 6. Repeatable 4-electrode (configured as 3 dipole channels) in vivo measurements have been made of naturally-occurring (physiological) ENG evoked by (a) stroking and (b) pricking with needles the tissue close to the animal's tail; 7. New data on sheep's physiological bladder function (during anaesthesia) have been acquired for future reference; in parallel nerve morphometry has been done on two controls. *******
First Year Of Impact 2018
 
Description Mr Justin Perkins Clinical Science and Services Large Animal surgeon / Dr Ludovic Pelligant Comparative Biomedical Sciences Large Animal anaesthetist 
Organisation Royal Veterinary College (RVC)
Country United Kingdom 
Sector Academic/University 
PI Contribution None to date.
Collaborator Contribution Helped to develop a research protocol for using sheep as a large animal model.
Impact None yet.
Start Year 2017
 
Description Research seminar RVC 23rd May 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Other audiences
Results and Impact This was a research seminar across two sites, relayed via conference call. This involved ~30 people, composed of scientists, veterinarians, researchers, post-docs or PhD students.
This triggered questions and discussion and was a local school event at the Royal Veterinary College, as part of their research seminar series.
Year(s) Of Engagement Activity 2018
 
Description Research seminar in a research university Texas A&M 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Around 50 academics, researchers and post-graduate students affiliated with Texas A&M University (in particular those in the College of Veterinary Medicine) attended a monthly research seminar of ~45 minutes. This allowed presentation of the EPSRC project and the sheep model used as part of this research as well as the method of 'velocity selective recording'. The talk was well received with a session after it for questions and discussions.
Year(s) Of Engagement Activity 2018
 
Description Talk at international congress and poster presentation 31st Annual Symposium of the ESVN-ECVN - September 2018 Copenhagen 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact International conference; talk associated with poster presentation; audience was composed of specialists neurologists and neuroscientists.

DETECTING SACRAL NERVE SIGNALS FOR ARTIFICIAL BLADDER CONTROL IN SPINAL CORD INJURY: A NEW CUFF ELECTRODE DESIGN

N. Granger1, B.W. Metcalfe2, T. Grego3, S. Sadrafshari2, N. Donaldson4, J. Taylor2.

1 The Royal Veterinary College, University of London, Hatfield, UK and CVS Referrals, Bristol Veterinary Specialists at Highcroft, Bristol, UK
2 Department of Electronic & Electrical Engineering, University of Bath, Bath, UK
3 Department of Medical Physics & Biomedical Engineering and Department of Mechanical Engineering, University College London, London, UK
4 Department of Medical Physics and Biomedical Engineering, University College London, London, UK
Year(s) Of Engagement Activity 2018