Abstract
A new approach to detect the onset of bladder contractions has been explored. During the long-term implantation (140 days) of a cuff electrode and a telemetric device on a sacral nerve root, both sensory and motor nerve signals related to mechanical manipulations of bladder and rectum could be measured.
Voidings and reflex bladder and rectal contractions were induced in the awake pig to measure neural reflex activity not seen before in acute, anaesthetized studies.
Introduction
People with spinal cord injury will often develop detrusor hyperreflexia. Detrusor hyperreflexia is characterized by unvoluntary bladder contractions at relative low volumes. If untreated, this can lead to incontinence, low bladder capacity and reflux of urine to the kidney. Conventional treatment options to prevent this problem include medication or surgical interventions, such as bladder augmentation or dorsal rhizotomy.
We are currently exploring a new approach to treat detrusor hyperreflexia. It has
been shown that electrical stimulation of afferent branches of the pudendal
nerves inhibits the micturition reflex [1].
Stimulation does not need to be continues but preferably only when a detrusor contraction occurs. This implies that a sensor is
needed to detect the onset of bladder contractions.
Implantable sensors with sufficient long
biocompatibility and reliability are difficult to build, but with the advent of
methods for long term electrical interfacing with nerves, recording from the
natural sensors in the human body have become a realistic alternative [2].
Recent acute studies have shown that afferent nerve signals related to
mechanical bladder activity can be recorded by using cuff electrodes placed on
the pelvic nerves or (dorsal) sacral roots in pigs [3], cats [4] and human
[5,6].
The main goal of this study was to measure sacral root
nerve signals on a chronic basis in an awake state and
in relation to bladder activity, so that reflex bladder contractions can be
detected.
Methods
A. Implant procedure
Three Göttingen mini-pigs (32-40 kg) have been implanted. The nerve cuff electrode and telemetric device [9] were implanted under general anaesthesia (Isoflurane) and under sterile conditions. A sacral laminectomy was performed to gain access to the sacral nerve roots. The nerve roots were identified by the response to electrical stimulation. The cuff electrode was placed on the sacral root which created the strongest response in bladder pressure to electrical stimulation. After measuring the electrode impedances in situ, the ENG was checked to contain afferent nerve signals after mechanical stimulation of the appropriate dermatome.
The wires
from the cuff electrode were routed subcutaneously from the distal end of the
cuff, and with a small loop to relieve stress, to the telemeter. The telemeter
was placed in the subcutaneous fatty tissue layer, between 1 and 2 cm deep,
about 15 cm cranial and lateral to the processus transversus of the lumbal
vertebrae.
B. Implanted devices
Nerve cuff electrodes were used to measure the
afferent nerve signals because they have been showen
to be suitable for long-tem recording of nerve activity in animals [7] and
humans [8]. The silicone (NuSil, MED-117) cuff
electrodes were 20 mm in length, had an inner diameter of 2.2-3.0 mm, and had
circular contacts made of either multistranded
stainless steel wire (Cooner wire, AS 634) or
platinum foil (25 µm thick, 1 mm wide). A reference electrode made out of the
same material was mounted on the outside of the cuff.
The ENG signals picked up by the cuff electrode were recorded using a telemeter system, specially designed for long-term recordings in animals and humans [9]. This system includes a chronically implantable amplifier/transmitter powered by an external control/drive unit through an inductive link.
C. Experimental procedure
Experiments were initially performed under general anaesthesia (Isoflorane). Two catheters were placed: In the bladder an open catheter and in the rectum a balloon catheter. Both catheters were connected to pressure transducers. The experimental protocol included:
- Electrical stimulation of the clitoral
nerve. To test the neural interface, compound sensory nerve action
potentials (CAPs) were elicited by electrical
stimulation of the clitoral nerve (1-32 mA, 8 Hz, 200 μs
duration) using a bipolar surface electrode placed on the Labium Majus. Noise was reduced by averaging CAPs.
- Rectal distention. The rectal balloon
consisted of a latex glove mounted on a standard catheter. To distend the
rectum, it was generally filled by two 100 ml bolus injections of saline. This
was followed by removing and re-injecting 50 ml, repeated for several times.
- Bladder fillings. Bladder fillings were done when the anaesthesia was turned off and the pig was in a stage of
waking up. The empty bladder was filled by either 100 ml saline boluses
injections until the bladder volume reached 300-400 ml, or by connecting the
bladder catheter to a saline bag positioned
50 cm above the pig. This difference in height let the saline flow freely into
the bladder.
In later experiments, from 98 days after implant, cystometries were performed with the awake pig placed in a restriction cage and using a roller pump for infusion (infusion rate: 60 ml/min).
D. Signal processing
The signal from the telemeter system was bandpass filtered (400 Hz-4 kHz) before being sampled (20 kHz), rectified, bin-integrated (Tbin of 50 ms) and, together with bladder and rectal pressure stored on PC. The bladder and rectal pressure, raw ENG and filtered ENG were also stored on a TEAC DAT-recorder.
Results
Experiments started two weeks after implantation. In all three pigs excellent nerve signals were obtained, but due to technical problems after week 3 in pig 1 and 2, most of the results presented here were obtained from the third pig.
Nerve cuff electrodes have been implanted on the S1 (1
pig) and S2 (2 pigs) sacral nerve root. Electrode impedance ranged from 900
Ω to 2 kΩ (at 1 kHz). At the present time,
the nerve cuff implanted in the third pig has been functioning without any
problems for more than 140 days. After 28 days, no signal could be obtained
from the telemeter because of a malfunction in the device. It was replaced 84
days post implant by a new device.
A. Compound sensory nerve action potentials
The quality of the neural interface is
examined by following the maximal peak-to-peak amplitude of the elicited
sensory compound nerve action potential over time. The amplitudes of the
averaged CAPs can be seen in Fig. 1 for pig 3. The
CAP amplitudes measured 14 days after implant in the pig 1 and 2 at supramaximal stimulation were 8.0 ± 1.3 µV and 22.2 ± 5.1
µV respectively.
Figure 1, The amplitude of the
electrically evoked CAPs for different stimulation currents as function of time.
B.
Rectal distention
In two out of the three anaesthetized pigs, an increase in afferent ENG could clearly be measured during rectal distentions 14 days after implant. A typical response is shown in Fig. 2.
Applying rectal distention in the awake pig was more difficult. The positioning and distention of the rectal balloon often triggered a defecation reflex, causing the balloon to be expelled. A rectal afferent response was difficult to detect because of amount of other neural signals, mostly from efferent origin.
Figure 2, Rectal distention in anaesthetized pig, 22 days post implant.
C. Bladder fillings
Bladder fillings, performed in all
three pigs, during 5 wake-up states resulted in 9 voidings.
In the third pig (with cuff on S1 nerve), a nerve signal correlating with the
bladder activity was seen. During 14 cystometries
performed in awake state, 24 voidings were observed.
Figure 3, Cystometry in the awake pig (#3), 126 days
post implant.
Infusion starts at t = 10s. Voiding starts at t = 43s and stops at t = 63s.
A typical bladder filling or cystometry in the awake pig is shown in Fig. 3. Movement artifacts were seen prior to and following voidings. Infusion was stopped when the voiding started. A small increase in baseline, caused by an increase of bladder and urethral afferent signals, can be seen during the voiding. The efferent signal inducing phasic urethral and perineal contractions, reflected in the bladder pressure (Pblad), were also measured in the ENG.
Discussion & Conclusions
It has been shown that it is possible to
measure sacral root nerve signals of different afferent origin on a long-term
basis, both with the pig anaesthetized and awake. Results also show that reflex
detrusor and rectal activity, usually suppressed by
the anaesthesia used in acute pig experiments, can be
induced in the awake state while the long-term implant makes it possible to
measure the neural signals involved.
Furthermore, the course of the CAP
amplitude resembles findings from other long-term implant studies [10]. The 4
mA stimulation created a nearly constant CAP over time (Fig. 1). Larger
variation in CAPs was seen at the supramaximal
stimulation intensities. These larger stimulation intensities made the pig
become restless, causing movement of the hand-held stimulation electrode with respect to the wanted stimulation site.
In the awake healthy pigs used in this study, the recorded sacral root nerve signal is composed of efferent as well as afferent signals innervating the different organs within the pelvic area. In SCI-patients however, the nerve signal can be expected to contain a much lower amount of efferent signal due to the absence of voluntary control. This is likely to be an advantage in the development of signal processing methods meant to detect bladder contractions from sacral nerve root signals.
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Acknowledgments: This work was supported by the Danish
National Research Foundation and the Danish Research Council.