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
Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.
People |
ORCID iD |
| Nicolas Granger (Principal Investigator) |
Publications
Donaldson N
(2023)
A Multielectrode Nerve Cuff for Chronic Velocity Selective Recording in a sheep model.
in Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference
Granger N
(2020)
Bladder and Bowel Management in Dogs With Spinal Cord Injury.
in Frontiers in veterinary science
Metcalfe B
(2021)
Urinary Bladder Innervation within the Sacral Roots of a Sheep
Metcalfe B
(2020)
Selective Recording of Urinary Bladder Fullness from the Extradural Sacral Roots.
in Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference
Prager J
(2024)
Baseline cystometric parameters in conscious and anesthetized sheep: experimental data and systematic review.
in American journal of veterinary research
Sadrafshari S
(2024)
CMOS Analogue Velocity-Selective Neural Processing System
in Electronics
Sadrafshari S
(2022)
The Design of a Low Noise, Multi-Channel Recording System for Use in Implanted Peripheral Nerve Interfaces.
in Sensors (Basel, Switzerland)
Taylor J
(2020)
The Effects of the Presence of Multiple Conduction Velocities in the Analysis of Electrically-Evoked Compound Action Potentials (eCAPs).
in Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference
| 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 importantly, 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. In the second part of our grant, we have continued to refine the method of implanting our new cuff electrode and we have designed a surgical tool to ease wrapping the cuff around the sacral nerve and allow close contact between nerve and electrode. This device also facilitates gluing the lead of the cuff. This method now seems effective. We have then designed a connector placed on the sheep's head that is connected to the sacral cuff electrode via silicone embedded cables. The head connector is made of titanium and covered with a structure that allows the skin to heal around it. This system allows us to connect recording devices at the head of the animals that can interrogate the cuff electrode placed around the sacral nerve innervating the bladder. The system is placed in surgery and the animal recovered and we know that this is safe. The animals live normally with the system in place (so far we have followed them up for 2 months) and this will allow us to study bladder physiology and nerve signals originating from the bladder while the animal is awake. During surgery, we have studied bladder electrical signals recorded through our cuff electrode. This has required a vast amount of engineering of amplifiers which has proved rewarding: we have now been able to reliably record bladder electrical signals while the bladder is being distended by sterile water in surgery. We observe a good correlation between increase in bladder pressure and nerve signals ascending from the bladder to the brain. We have tested the effect of different anaesthetic drugs on bladder pressure in sheep as well. We are in a phase of analysing the electoral signals from the recordings we have done. We have acquired a vast amount of recordings and the analysis is on going but preliminary findings are promising. We now need to move onto awake recordings during bladder distension with sterile water, which will generate further data. We know that it is possible to inflate the bladder with a catheter placed in the bladder of the sheep awake. We are also planning to conduct recordings while the sheep is walking on a treadmill. We have faced problems with external interferences (radio-frequency signals) around our recording rooms and are working on fixing this. But the background noise measures within the sheep are very good so far in awake implanted animals. We are also in the process of describing the anatomy of the sheep sacral system, which is not clearly known. To date, March 2021, we have continued to exploit the sheep model and included a further 12 animals in experiments in 2020. This has followed our original plans and we have made significant advances with these animals. a. Seven animals were used in chronic experiments: during these experiments, we implanted sacral roots with our cuff electrode and recorded at implantation the sensory signals from the bladder during filling, the impedance of the cuff electrode; we then recovered the sheep and conducted awake recordings during bladder filling or walking on a treadmill and measured impedance again. The animals were kept for 1 month to 9 months. Advances made during these experiments include: (i) refinement of signal processing by testing and designing different amplifier; removing background noise from environment and animal; (ii) acquisition of sensory signals in awake animals; (iii) improvement of surgical protocols for implantation of the cuff electrode using new implantation tools; (iv) collection of histopathological data allowing to compare the spectrum of nerve diameters to the spectrum of signal velocities recorded from the cuff electrode. We are now in the process of analysing the sensory signal data. The histopathology data is acquired and we are finishing the last two animals in 2 weeks, at which point data collection will be complete. b. Five sheep were used in terminal experiments during which we implanted systemically and bilaterally 4 pairs of sacral roots with book electrode to establish the different contributions of each pair to bladder innervation; this has generated data so far unknown. Overall, we have continued to establish our model as a useful platform to study bladder neurophysiology. We believe that this will serve to future projects and in particular, the next crucial step will be to establish a method to link the recording cuff electrode to an implantable device communicating with the motor sacral roots for live bladder control. Third phase of the grant, i.e. 2021-end: - We have fixed electrical interference we had during live recording in awake sheep, in part by using a building shielded from external radio-frequency signals; - We have included a further 5 animals into long term and recovery experiments and followed animals for up to 9 months; these animals did not show any neurological issues or complications of the surgery; we could record bladder activity from these animals awake and, in two cases, at the final recording point asleep; the data collected has been analysed now by a post-doc from Bath University appointed for 6 months for this work. The data is now prepared to be presented in a manuscript that will present the bulk of our data on chronic detection of bladder sensory signal; it will also present a new method of signal processing and the mathematical tools for analysing recording rapidly and now known; - Another manuscript is being prepared that will present acute recordings using book electrodes in 5 sheep and testing and comparing 4 sacral roots; - We have submitted a manuscript to three journals presenting the baseline cystometric measures obtained from the sheep; the manuscript so far has not been accepted but we are re-submitting it and perceive that the data will eventually reach an audience; manuscript available to view. - We are preparing a manuscript reporting the morphometric data of the sacral nerves in the sheep; the nerves have all been analysed using toluidine blue staining and this data will be send to a pathology / anatomy journal. - finally, we collected the head connector from the animals and these have been imaged with CT and histology; the data illustrate the use of hydroxyapatite as an interface between skin an environment and we have seen good integration of the sub-cutaneous tissue to the hydroxyapatite; the data is exploited by Dr Henry Lancashire, UCL. In summary, we have reached a phase of writing our results and will dedicate 2022 to this task. Publication of the results will allow us to built future research avenues. March 2023: we are now in a phase of analysing data and publishing our findings. Of importance, we have have the following results: 1. We have prepared and submitted a manuscript that reports the design, implantation technique and stability (through impedance measures) of a chronic extra-dural sacral implant in one animal; in this case, we have obtained 189 days follow-up. This is important because it demonstrates the manufacturing and performance of a neural interface for chronic monitoring of bladder nerve afferents with applications in urinary incontinence and retention management following spinal cord injury. Manuscript title: A Multielectrode Nerve Cuff for Chronic Velocity Selective Recording in a sheep model; authors: N. Donaldson, T. Grego, H. Lancashire, Member, IEEE, J. Prager, N. Granger, B. Metcalfe, Member, IEEE & J. Taylor, Member, IEEE; manuscript under review; conference paper: 45th Annual International Conference of the IEEE Engineering in Medicine and Biology Society. We are planning to complete this report with another publication reporting the actual sensory recordings through velocity selective recording in 6 chronic sheep. 2. We have prepared a manuscript (not yet submitted for review) to report acute recordings from sacral nerve roots in non-recovery sheep experiments: this report reveals the afferent pathways of the urinary bladder in sheep using extra-dural book electrode recordings similar to the canine book electrodes we worked on before manuscript; it demonstrates that the afferent activity in response to bladder filling varies between sacral nerve roots and therefore offers a map of the bladder sensory innervation. Proposed title: Afferent pathways of the urinary bladder in sheep: Recordings from the extradural sacral roots; authors: Jon Prager, Martin Leonhardt, Leen Jabban, Nicolas Granger, John Taylor, Nick Donaldson and Benjamin Metcalfe 3. We have prepared and submitted a manuscript reporting baseline cystometry data in normal sheep; this corresponds to some useful background work and data we acquired during the project and forms useful information that other researchers could use if they use the sheep model to study urinary function. Manuscript title: Cystometric assessment of bladder function for sacral neuromodulation in conscious or anaesthetised sheep; Jon Prager, Benjamin Metcalfe, Shamin Sadrafshari, John Taylor, Nick Donaldson, Nicolas Granger; manuscript was rejected from Spinal Cord but is reshaped for American Journal of Veterinary Research. 4. We have published the design of the multi-electrode cuff electrode, describing the engineering parameters of this system: this work highlights the critical importance of understanding the effect of interface circuits on the performance of neural recording systems. The Design of a Low Noise, Multi-Channel Recording System for Use in Implanted Peripheral Nerve Interfaces; authors: Shamin Sadrafshari, Benjamin Metcalfe, Nick Donaldson, Nicolas Granger, Jon Prager, John Taylor; Sensors (Basel). 2022 Apr 30;22(9):3450. doi: 10.3390/s22093450.DOI: 10.3390/s22093450. |
| Exploitation Route | We have presented the design of our implant at a conference and we have now made this available through publication - see above publications. This implant can be exploited by others for further testing in view of recording sensory signals from nerves. In the particular example 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 community, engineers working with implantable materials, and doctors in particular. We have established a sheep model that posses a cuff electrode placed around sacral nerves connected through a cable to an interface at the head. This allows to connect a cable onto a connector at the head and interrogate sacral nerve with the animal awake. This 'preparation' is completely new, feasible in our hands and appears safe and painless in animals who can leave with the cuff electrode and the connector at the head. Therefore, this model could be used by other researchers to study various questions related to bladder physiology, or potentially study pathological conditions that can be created in this model. If is also conceivable that the model can be used for other nerves (i.e. vagal nerve), by using the same interfaces (cuff and connector fixed on the head). We have also gathered electrophysiological recordings from the bladder during filling and the result of this needs to be further analysed, and we have now a manuscrit under review reporting results for one chronically implanted animal. Our data will constitute extremely valuable data describing bladder physiology, thus far unknown. We also possess urodynamic and anatomical data as well in the sheep now, which were not known before and we are planing to describe these. As the project has progressed, we have collected post-mortem sacral nerve samples that we are currently analysing with histopathology and axonal markers to look at the distribution of axons along the sacral nerves in sheep and the reactions caused by our cuff implant. The final data has now been analysed (from acute anaesthetised sheep but also chronic awake sheep) and the method of analysis will be published - see above manuscripts in preparation. It utilises new mathematical methods and these will be available to other researchers wishing to extract bladder signal and will allow much faster data processing. The anatomical / histopathological results on sheep sacral nerve will form a new set of baseline data that can be built on, in particular comparing the anatomy pre and post implantation of recording electrodes in that region. The data on hydroxyapatite / skin interaction strengthens knowledge on integration of implants in the body. |
| Sectors | Electronics Healthcare Manufacturing including Industrial Biotechology Pharmaceuticals and Medical Biotechnology |
| Description | Our findings can be used in healthcare in the development of live nerve signal processing in surgery, in particular for the purpose of bladder signal detection. We have also obtained new funding looking at modelling the bladder and our previous data has allowed validation of such models. These are engineering models that can avoid use of animals and be used to probe paradigms before refinement in experimental animals. |
| First Year Of Impact | 2023 |
| Sector | Healthcare,Manufacturing, including Industrial Biotechology |
| Description | Restoration of urinary function in spinal injury using olfactory ensheathing cell transplant combined with bladder nerve electrical stimulation |
| Amount | £136,658 (GBP) |
| Organisation | International Spinal Research Trust (Spinal Research) |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 08/2020 |
| End | 03/2024 |
| Title | Sacral cuff electrode implantation device and head connector for live bladder ascending signal recording |
| Description | We have created a sheep model including implantation of a sacral cuff electrode (implanted with a new surgical tool) and a connector fixed on the skull and breaching the skin via a hydroxyapatite interface (therefore that can be interrogated from the animal awake). The cuff can then be interrogated with the animal awake during movement and bladder filling. This 'preparation' is new and has never been done. |
| Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
| Year Produced | 2020 |
| Provided To Others? | No |
| Impact | We have not published on this yet and therefore not had any impact yet but intend to do so in the near future. |
| Description | Dr Henry Lancashire Engineering of implantable devices |
| Organisation | University College London |
| Department | Faculty of Engineering Sciences |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | We provided a large animal model to assess inclusion of sub-cutaneous tissue within hydroxyapatite as a method to form a waterproof barrier between internal organs and environment. |
| Collaborator Contribution | The collaboration also led to further development of book electrodes for use in rats and wireless methods of sacral nerve stimulation in rats using purpose built cages. |
| Impact | None so far. |
| Start Year | 2021 |
| 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 | Professor Richard Piercy MA VetMB MS PhD Dip ACVIM MRCVS Professor of Comparative Neuromuscular Disease |
| Organisation | Royal Veterinary College (RVC) |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Prof. Piercy is Professor of Comparative Neuromuscular Disease at the Royal Veterinary College. He is an RCVS recognised specialist in Equine Internal Medicine and a Diplomate of the American College of Veterinary Internal Medicine. He directs the Comparative Neuromuscular Disease Laboratory at the RVC. His clinical work mainly involves horses with neurological and neuromuscular problems. Within our project, he is hosting the histopathology work we do on sheep sacral nerves. Our collaboration brings a new species in his lab and allows to validate methods used for other species to sheep. |
| Collaborator Contribution | Prof. Piercy's lab allows us to run histopathology techniques he uses for large animal peripheral nerves (mainly in horses) that perfectly fits what we are trying to achieve with our sheep specimens. |
| Impact | No output yet |
| Start Year | 2019 |
| Description | Abstract accepted at a national conference - The British Neuroscience Association |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Professional Practitioners |
| Results and Impact | Baseline sacral nerve morphometry and cystometry in a sheep model use to record urinary bladder fullness through a sacral neuroprosthesis J. Prager, B. Metcalfe, N. Donaldson, J. Taylor, N. Granger The British Neuroscience Association - 12th to 15th Apr 2021. BNA2021 Festival of Neuroscience |
| Year(s) Of Engagement Activity | 2020 |
| Description | Abstract accepted at an international conference - 10th International IEEE/EMBS Conference on Neural Engineering |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | Is it feasible to detect bladder pressure from a cuff at the extradural sacral roots? Experiments in sheep N. Donaldson, J. Prager, B. Metcalfe, Member IEEE, N. Granger and J. Taylor 10th International IEEE/EMBS Conference on Neural Engineering (NER) May 4-6 2021 Urinary Bladder Innervation within the Sacral Roots of a Sheep B. Metcalfe, N. Granger, J. Prager, L. Jabban, J. Taylor, S. Sadrafshari, N Donaldson 10th International IEEE/EMBS Conference on Neural Engineering (NER) May 4-6 2021 |
| Year(s) Of Engagement Activity | 2020 |
| Description | British Veterinary Neurology Society Annual meeting 3.04.2019 |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Professional Practitioners |
| Results and Impact | Gave a 40 minutes talk in front of ~100 audience of veterinary surgeons, post-graduate student, PhD students, veterinary neurosurgeons and human neurosurgeons. This was a formal lecture with questions in the end. Title was: 'Spinal cord injury: can we repair or bypass'. |
| Year(s) Of Engagement Activity | 2019 |
| Description | Conference - invited, International |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | Physiology of micturition and defecation IV INTERNATIONAL PROFESSIONAL CONFERENCE PURINA PARTNERS Moscow December 2020 Management of urinary and faecal incontinence after spinal cord injury IV INTERNATIONAL PROFESSIONAL CONFERENCE PURINA PARTNERS Moscow December 2020 |
| Year(s) Of Engagement Activity | 2020 |
| Description | Conference - invited, International |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | Urinary complications of spinal cord injury in dogs: management and new treatments Unisvet Congress, XV Veterinary National Congress, Italy, February 2020 |
| Year(s) Of Engagement Activity | 2020 |
| Description | Congress presentation Chronic spinal cord injury: bypassing the lesion for artificial bladder control |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | Chronic spinal cord injury: bypassing the lesion for artificial bladder control Spinal cord injury causes dramatic physiological changes to bladder function in dogs and in humans. Spinal-injured individuals live with long-term neurologic impairments, including lower urinary tract dysfunction considered by many to be the most unacceptable because of the associated physical and social consequences. In companion dogs, there is also an unknown proportion of chronically paraplegic animals cared for by their owner and experiencing urinary dysfunction. This is often the result of intervertebral disc herniation in the thoraco-lumbar region but other injuries such as ischemic are recognised to commonly lead to persistent urinary tract dysfunction despite recovery of locomotion. Supra-sacral spinal cord injury and bladder dysfunction Supra-sacral spinal cord injuries are lesions of the spinal cord above the sacral segments locally controlling bladder function (Hu et al., 2016). Supra-sacral spinal cord injury causes dysfunction of urine storage and voiding: during bladder filling, the detrusor constituting the muscular layer of the bladder becomes overactive, leading to involuntary urine loss; during urine voiding, detrusor-sphincter dyssynergia, a mismatch between the detrusor and sphincters leading to lack of sphincter relaxation while the detrusor contracts, results in inefficient voiding and high bladder residual volume. There is therefore a state of urinary incontinence and urinary retention. Affected individuals require intermittent bladder catheterization or manual bladder emptying, which is known to be a relatively inefficient method. There are many secondary complications, which include: (1) recurrent lower urinary tract infections but also ascending infection to the kidneys (i.e., pyelonephritis), spread of infection through the blood and selection for multi-drug resistant uropathogens; (2) damages to the kidneys resulting from elevated intravesical pressure and reflux of urine from the bladder to the kidneys; and in humans, (3) bladder distension-mediated autonomic dysreflexia, a phenomenon causing hypertension when the bladder is overly distended, and associated increased risk of stroke. Renal diseases cause ~13% of humans with chronic spinal cord injury to die. The death rate in canines is less well known than in humans. In a case series of 34 dogs with chronic spinal cord injury (>3 months paraplegia and bladder dysfunction) and followed for 6 months, we found 17 urinary tract infections from 212 samples in 11 dogs (32% of the cases) and 7 of these dogs died over the 6 months period, of which 3 from kidney failure (personal unpublished data). In another study of 47 dogs, 35 dogs had at least 1 positive urine culture and there was no clear link between bacteriuria and cause of death (Rafatpanah Baigi et al., 2017) A major problem with spinal cord injury is the difficulty to repair the lesions. This is in part due to the complexity of the damaged region and our limited ability, currently, to exploit the understanding of the pathophysiology we have gained over the years. Nevertheless, the effector organs below the lesion, such as the bladder, remain viable despite being disconnected from higher centres and therefore, there is an opportunity to control these via their peripheral innervation. Peripheral nerves conduct motor or autonomic information to the effector organs and transmit sensory or autonomic information from the effector organs to the central nervous system. Accessing and controlling this information would allow artificial control of the target organs. Characterization of bladder dysfunction with supra-sacral injuries Characterization of bladder dysfunction is a first essential step in companion dogs to understand the pathophysiological changes associated with supra-sacral spinal cord injury and later assess the effect of therapies. Urodynamic measurements offer a method to evaluate bladder function; in humans they greatly improve decision-making for management and therefore can influence clinical outcome. Using urodynamic measures, we have quantified bladder physiology in 84 chronically paraplegic dogs (>3 months paraplegia) and found that: (i) their bladder capacity was ~73% less than normal dogs; (ii) 69% of cases had urine leakage before reaching their expected capacity volume; (iii) 55% had unprovoked involuntary detrusor contractions during bladder filling; and (iv) 69% had reduced bladder compliance (defined as <12.5mL/cmH2O) (personal unpublished data). This altogether suggests reduced compliance. In the acute phase of spinal cord injury, we collected a set of measures in 45 paraplegic dogs and found, amongst other measures, that 13 cases (~29%) had 'normal' compliance, 2 cases (~4%) had a 'high' compliance (defined as >40mL/cmH2O) and 30 cases (~67%) had a 'low' compliance (again defined as <12.5mL/cmH2O). A small number of studies have looked at the effect of various medications such as cholinergic drugs (e.g., bethanechol), a-sympatholytic drugs (e.g., prazosin) or benzodiazepine but no clear effect has been detected. Addressing urinary retention The problem of retention can be partially solved by using sacral nerve electrical stimulation. This has been tested for a long time in the laboratory, in large animal models (including experimental cats and dogs) but also more recently in companion dogs. Sawan et al., (1993) first tested an implantable system for computer-controlled bladder emptying in experimental spinal cord injured dogs. Wang et al., (2002) further studied four experimental spinal cord injured dogs receiving S2 sacral electrodes and controlled bladder emptying during stimulation. In humans, a neuroprosthesis for controlling the bladder after spinal cord injury was developed by Brindley (1994) some 30 years ago and remains the only clinically implantable device for bladder control in people and is currently used world-wide. We translated this technique to companion dogs (with chronic T3-L3 spinal cord injury, paraplegia and urine retention) using a dog-specific electrode and in the vast majority, stimulation of the pair of S2 sacral nerves provides adequate bladder contraction, pressure and efficient voiding (Granger et al., 2013). In 30 companion dogs treated in that way, two dogs developed post-operative infections resulting in euthanasia in one case, two developed short-lasting seromas; none of the dogs died from urinary complications and 8 dogs have died during the follow-up (an average of 886 days) so far, while 5 dogs have had their bladder emptied daily by the owner for more than seven years (personal unpublished data). Sacral root stimulation is not a perfect system because the stimulation activates both sensory and motor roots (when done extra-durally) and this leads to detrusor-sphincter dyssynergia (there is sphincter contraction while the detrusor is contracting) and a voiding phase in 'bursts' of urine, rather than free flow of urine. To overcome this issue in humans, a dorsal (sensory) root rhizotomy is performed at the time of the sacral neuroprosthesis implantation, leaving only the motor root functional for stimulation. But this surgical rhizotomy is not reversible and disliked by patients. The unwanted sphincter contractions can be prevented by blocking the pudendal nerves bilaterally using high-frequency current (at about 2 kHz). This blockade is reversible and is only needed during voiding (Boger et al., 2008). This high frequency blocking is a recently introduced method that is already being used in devices for blocking pain signals after amputation without any indication of nerve damage (Wataaja et al., 2011). However, the best timing of this high frequency blocking before and during micturition is not known and requires further research (see below). Addressing urinary incontinence In the chronic phase of spinal cord injury, neurogenic bladder over activity and reduce bladder compliance develop, leading to incontinence. The extend and impact of this clinical sign in dogs and on their owner is not documented, perhaps because the owner do not report this to veterinary surgeons in the chronic phase of spinal cord injury. However, this is a well-documented issue for humans living with paralysis. To combat bladder over-activity, local interventions on the bladder are currently proposed to humans in the form of botulinum toxin A injections and is reported to greatly improve incontinence and quality of life, but not the best long-term solution (Chen et al., 2020). Oliveira et al. (2019) investigated intravesical administration of resiniferatoxin during spinal shock in experimental rats and found long lasting reduction of intravesical pressures and amplitude of bladder contractions. In dogs with naturally occurring spinal cord injury, Levine et al. (2017) demonstrated that the administration within 48 hours of injury of a broad-spectrum matrix metalloproteinases inhibitor, targeting the bladder wall structure, improves bladder compliance. Incontinence can also be managed by low intensity electrical stimulation of the large afferents in the pudendal nerve (Nakamura & Sakurai, 1984, Yang et al., 2014) or sacral posterior roots (Kirkham et al., 2002) a technique called neuromodulation, which suppresses the voiding reflex. For an in-depth review, see Sanford & Suskind, (2016). Future directions for artificial bladder control In spite of the developments presented above, at present, two requirements for a complete, practical neuroprosthesis are missing. Firstly, no satisfactory, practical method exists for detecting the onset of bladder contractions, bladder volume or pressure, that could be used to trigger neuromodulation in a chronic implant. Secondly, no method is available to 'inform' the patient of the level of bladder fullness to indicate when the bladder should be emptied. Afferent fibres from the bladder wall reach the spinal cord via the posterior sacral roots and are part the mixed extradural root. A landmark study investigated the use of tripolar microchannels for detection of bladder activity at the intrathecal roots in rats (Chew et al., 2013). This method requires that the dura around the spinal cord be opened (durotomy) and as such presents several risks such as damage to the delicate and intrathecal roots at that level, spinal fluid leak post-operatively and long-term damage to the roots themselves. This represents a significant deterrent to the uptake of a new device. An alternative site for the electrodes is the extradural roots. Electrodes are routinely implanted here by some surgeons in the Brindley procedure. Recently, a closed-loop sacral neuromodulation system (Ouyang et al., 2022) was set-up in experimental anesthetised cats: Ouyang and colleagues used successfully real-time neural recordings from dorsal root ganglia to inform on bladder pressure and initiate sacral root electrical stimulation when detecting an increase in bladder pressure. There remains the need to do this in awake mammals. We have obtained sensory bladder recording in anesthetised companion dogs during surgery from teased extra-dural sacral nerves; however, we were not successful at chronically recording these signals and proposed to move to a sheep model, following Brink et al. (2015). The conduction velocity of the sensory (myelinated) afferent fibres from mechanoreceptors of the genital region in sheep is ~41.4 m/s (+/- 14.7 m/s), similar to bladder afferents coding for pressure and volume information in man, 38 and 41 m/s respectively. To discriminate between these signals, it is possible to use a method called velocity selective recording (Taylor et al., 2004, Donaldson et al., 2008). The principle of velocity selective recording is based on the fact that action potentials propagate at specific velocities and that these velocities are related to the nerve fibre function (for myelinated nerves). Recording the velocity spectrum of neural traffic therefore provides a signature relating the recorded signals to their function (and also discriminate between afferent and efferent traffic on a mixed nerve, such as extradural bladder nerves). The method requires multi-electrode cuffs and we have used such devices with as many as 11 electrodes along the length of a nerve cuff. Velocity selective recording is now established as a powerful technique for the analysis of electrically evoked electroneurograms (Schuettler et al., 2013). In a series of sheep, we have successfully detected bladder fullness signals during filling cystometry using our multi-electrode cuffs placed around extra-dural 'peripheral' sacral nerves (S2 or S3) first in anesthetised sheep and then in awake chronically implanted animals for up to 6 months (Sadrafshari et al., 2022; Metcalfe et al., 2020). The signal processing however remains a challenge and is difficult to do in real-time. Extraction of the signal also still necessitates a device breaching the skin and a wireless method is needed. Therefore, there are two key steps to take the current knowledge to the next level: (i) creating an implantable servomechanism able to analyse in real time sensory signals and return a command; and (ii) being able to communicate with the servomechanism remotely without breaching the skin in an awake patient. References Hu HZ, Granger N, Jeffery ND. Pathophysiology, Clinical Importance, and Management of Neurogenic Lower Urinary Tract Dysfunction Caused by Suprasacral Spinal Cord Injury. J Vet Intern Med. 2016 Sep;30(5):1575-1588. Rafatpanah Baigi S, Vaden S, Olby NJ. The Frequency and Clinical Implications of Bacteriuria in Chronically Paralyzed Dogs. J Vet Intern Med. 2017 Nov;31(6):1790-1795. Sawan M, Duval F, Hassouna M, Li JS, Elhilali MM. A transcutaneous implantable bladder controller. Neurourol Urodyn. 1993;12(3):281-4. Wang S , Chunlin Hou, Aimin Chen, Shimin Zhang, Yingmin Diao, Chenghui Yin, Jinwu Wang, Ruisheng Xu, Wei Zhang, Mengjie Zhang. Bladder controller in bladder function reconstruction of paraplegic dogs. Zhonghua Wai Ke Za Zhi. 2002 Oct;40(10):780-2. GS Brindley, The first 500 patients with sacral anterior root stimulator implants: general description, Paraplegia, 1994, 32, 795-805. N Granger, D Chew, P Fairhurst, J W Fawcett, S P Lacour, M Craggs, C A Mosse, N Donaldson, N D Jeffery Use of an implanted sacral nerve stimulator to restore urine voiding in chronically paraplegic dogs. J Vet Intern Med. 2013 Jan-Feb;27(1):99-105. Boger A et al, Bladder voiding by combined high frequency electrical pudendal nerve block and sacral root stimulation, Neurourol Urodyn, 2008, 27, 435-39. J Wataaja, K Tweden and C Honda, Effects of high frequency alternating current on axonal conduction through the vagus nerve, J Neural Eng., 2011, 8, 056013. Chen SF, Kuo HC. Will repeated botulinum toxin A improve detrusor overactivity and bladder compliance in patients with chronic spinal cord injury? Tzu Chi Med J. 2020 Jul 29;33(2):101-107. Effects of early intravesical administration of resiniferatoxin to spinal cord-injured rats in neurogenic detrusor overactivity. Oliveira R, Coelho A, Franquinho F, Sousa MM, Cruz F, D Cruz C.Neurourol Urodyn. 2019 Aug;38(6):1540-1550. Levine JM, Cohen ND, Fandel TM, Levine GJ, Mankin J, Griffin JF, Kerwin SC, Boudreau CE, Trivedi A, Noble-Haeusslein LJ. Early Blockade of Matrix Metalloproteinases in Spinal-Cord-Injured Dogs Results in a Long-Term Increase in Bladder Compliance. J Neurotrauma. 2017 Sep 15;34(18):2656-2667. M Nakamura, T Sakurai, Bladder inhibition by penile electrical stimulation, Br J Urol, 1984, 56, 413-5. Yang G, Wang J, Shen B, Roppolo JR, de Groat WC, Tai C. Pudendal nerve stimulation and block by a wireless-controlled implantable stimulator in cats. Neuromodulation. 2014 Jul;17(5):490-6; A Kirkham et al, Neuromodulation of sacral nerve roots 2 to 4 with a Finetech-Brindley sacral posterior and anterior root stimulator, Spinal cord, 2002, 40, 272-81. Sanford MT, Suskind AM. Neuromodulation in neurogenic bladder. Transl Androl Urol. 2016 Feb;5(1):117-26. D Chew et al, A microchannel neuroprosthesis for bladder control after spinal cord injury in rat, Science Trans. Med., 5, 210ra155 (2013). Ouyang Z, Barrera N, Sperry ZJ, Bottorff EC, Bittner KC, Zirpel L, Bruns TM. Closed-loop sacral neuromodulation for bladder function using dorsal root ganglia sensory feedback in an anesthetized feline model. Med Biol Eng Comput. 2022 May;60(5):1527-1540. Brink T et al, A chronic, conscious large animal platform to quantify therapeutic effects of sacral neuromodulation on bladder function, J Urology, vol 194, 252-258, July 2015. Taylor T, J Winter and N Donaldson, The use of multiple-electrode nerve cuffs for low velocity and velocity-selective neural recording. Med. & Biol. Eng. & Comput., 42 (5), 634-43. Donaldson N, J Taylor, R Rieger and M Schuettler, Noise and Selectivity of Velocity-Selective Multi-Electrode Nerve Cuffs" Med. & Biol. Eng. & Comput., 46 (10), 1005-1018, 2008. Schuettler M, N Donaldson and J Taylor Fibre-Selective Recording from Peripheral Nerve of Frog Using a Multi-Contact Cuff Electrode, J. Neural Eng., 10 (2013) 036016. Sadrafshari S, Metcalfe B, Donaldson N, Granger N, Prager J, Taylor J. The Design of a Low Noise, Multi-Channel Recording System for Use in Implanted Peripheral Nerve Interfaces. Sensors (Basel). 2022 Apr 30;22(9):3450. doi: 10.3390/s22093450. Metcalfe B, Granger N, Prager J, Sadrafshari S, Grego T, Taylor J, Donaldson N. Selective Recording of Urinary Bladder Fullness from the Extradural Sacral Roots. Annu Int Conf IEEE Eng Med Biol Soc. 2020 |
| Year(s) Of Engagement Activity | 2022 |
| Description | EMBC 2020 Montreal conference papers - 3 papers submitted |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | Three papers submitted for EMBC 2020 conference 42nd Annual International Conferences of the IEEE Engineering in Medicine and Biology Society in conjunction with the 43rd Annual Conference of the Canadian Medical and Biological Engineering Society July 20-24, 2020, Montréal, Québec, Canada; (1) B. Metcalfe, N. Granger, J. Prager, S. Sadrafshari, J. Taylor and N. Donaldson; Selective Recording of Urinary Bladder Fullness from the Extradural Sacral Roots (2) J Taylor, S. Sadrafshari, N. Donaldson, N Granger, J Prager and B Metcalfe; The Effects of the Presence of Multiple Conduction Velocities in the Analysis of Electrically-Evoked Compound Action Potentials (eCAPs) (3) S. Sadrafshari, N. Donaldson, N Granger, B. Metcalfe, J Prager and J. Taylor; The Design of a Low Noise, Multi-Channel Interface System for use in Noisy Recording Environments |
| Year(s) Of Engagement Activity | 2020 |
| Description | NSpine 1.07.2019 - Innovative Spine Education - conference; gave a talk |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Professional Practitioners |
| Results and Impact | The activity was a couple of 15-20' talk that I gave in front of an audience of~25 people in one of the satellite meeting room of NSpine; one talk was a short lecture and one talk was a case example; the topic was 'Chronic complications of spinal cord injury'; the end of the session was a round table around complications of spinal cord injury; the primary focus of my talk was urinary incontinence, which was discussed during the round table.The round table involved human and vet neurosurgeons. |
| Year(s) Of Engagement Activity | 2019 |
| Description | Podcast on urinary incontinence |
| Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Public/other audiences |
| Results and Impact | I presented a podcast as part of 'The Veterinary Rehabilitation Podcast' presented by Dr Megan Kelly; this was entitled 'incontinence' and is a 30 minutes recording. |
| Year(s) Of Engagement Activity | 2019 |
| Description | Poster presentation Afferent Pathways of the Urinary Bladder in Sheep: Recordings from the Extradural Sacral Roots ECVN congress 2023 |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | Poster presentation: Afferent Pathways of the Urinary Bladder in Sheep: Recordings from the Extradural Sacral Roots Jon Prager1,2*, M Leonhardt3, L Jabban3, M Petrou3, N Granger1,2, J Taylor3, N Donaldson4, B Metcalfe3 Conclusions: The S2 root provides the most reliable afferent bladder signal S2 and S3 root stimulation causes the largest bladder pressure increase The S2 root may have the greatest afferent bladder activity, but efferent activity may be modulated primarily via S2 and S3 |
| Year(s) Of Engagement Activity | 2023 |
| 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 1.02.2018 |
| 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 |