Multiple Pudendal Sensory Pathways Reflexly Modulate Bladder and Urethral Activity in Patients With Spinal Cord Injury

Transcription

1 Multiple Pudendal Sensory Pathways Reflexly Modulate Bladder and Urethral Activity in Patients With Spinal Cord Injury Paul B. Yoo,*, Eric E. Horvath, Cindy L. Amundsen, George D. Webster and Warren M. Grill From the Departments of Biomedical Engineering (PBY, EEH, WMG), Neurobiology (WMG), Obstetrics and Gynecology (CLA) and Surgery (WMG, GDW), Duke University, Durham, North Carolina Purpose: Electrical stimulation of pudendal afferents can evoke reflex bladder contractions with relaxation of the external urethral sphincter in cats. This voiding reflex is mediated by pudendal sensory fibers innervating the penile and prostatic urethra that engage spinal and spinobulbospinal micturition pathways, respectively. However, clinical translation of this potential therapy in individuals with spinal cord injury is limited by the lack of evidence showing analogous reflex mechanisms in humans. We investigated excitatory pudendal-to-bladder reflexes in 7 individuals with chronic spinal cord injury. Materials and Methods: We recorded isovolumetric bladder pressure and perineal electromyogram in response to intraurethral electrical stimulation at varying amplitudes and frequencies. Results: Selective electrical stimulation of the proximal ( cm H 2 O) and distal urethral ( cm H 2 O) segments evoked sustained reflex bladder contractions in different subsets (3 each) of participants. In contrast, the corresponding reflex perineal electromyogram revealed a differential activation pattern between proximal and distal intraurethral stimulation (normalized electromyogram of and , respectively, p 0.05). Conclusions: To our knowledge we report the first clinical evidence of 2 independent excitatory pudendal-to-bladder reflex pathways, which in turn differentially modulate efferent pudendal output. Each reflex mechanism involves complex interaction of multiple sensory inputs and may provide a neural substrate to restore micturition after spinal cord injury. Key Words: urinary bladder, urethra, spinal cord injuries, reflex, urination SPINAL cord injury between the brainstem and the lumbosacral spinal cord can result in neurogenic detrusor overactivity and bladder-external urethral sphincter dyssynergia. 1 The disruption of descending supraspinal activity leads to changes in the synergic modulation of the spinal autonomic (parasympathetic and sympathetic) and somatic activity that regulates the lower urinary tract. 2 Despite treatment with anticholinergic medications and intermittent catheterization bladder dysfunction in individuals with SCI remains a significant problem with substantial adverse impact on quality of life. 3 Independently of the brainstem the spinal cord can mediate reflexes with clinical relevance for restoring urinary function. For example, activity in afferents of the DGN of the pudendal nerve can activate a bladder inhibitory reflex. Studies in cats 4,5 and in humans with SCI 6 8 showed ro- Abbreviations and Acronyms BCR bulbocavernosus reflex CSN cranial sensory nerve derived from pudendal nerve DE distention evoked DGN dorsal genital nerve EMG electromyogram IU intraurethral P det detrusor pressure SCI spinal cord injury T stimulation threshold Td distal urethral T Tp proximal urethral T V th volume threshold Submitted for publication April 8, Study received Duke University Medical Center institutional review board approval. Supported by the Craig H. Neilsen Foundation and National Institutes of Health R01 NS * Correspondence: Department of Biomedical Engineering, Duke University, Hudson Hall, Room 136, Box 90281, Durham, North Carolina ( paul.yoo@duke.edu). Financial interest and/or other relationship with Microtransponder. Financial interest and/or other relationship with St. Jude Medical. Financial interest and/or other relationship with American Medical Systems and Life-Tech. Financial interest and/or other relationship with NDI Medical, Medtronic, Boston Scientific and Stryker /11/ /0 Vol. 185, , February 2011 THE JOURNAL OF UROLOGY Printed in U.S.A by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC. DOI: /j.juro

2 738 PUDENDAL SENSORY PATHWAYS MODULATE BLADDER AND URETHRAL ACTIVITY bust inhibition of bladder contraction and increased cystometric capacity by low frequency (3 to 20 Hz) stimulation of DGN fibers. However, our understanding of a complementary excitatory pudendal-to-bladder reflex in human remains incomplete. Experimental evidence in cats showed that activity in pudendal afferents can generate reflex bladder contraction and voiding 4,9,10 but evidence of an analogous reflex in humans is limited. 11,12 Also, the inability to identify the stimulated nerve fibers and incomplete knowledge of the somatic sensory innervation of the lower urinary tract 13,14 make it difficult to interpret the effects of electrically stimulating different afferent pathways on bladder reflexes. A recent study in cats showed that innervation of the proximal (prostatic) and distal urethra occurs via 2 independent branches of the pudendal nerve, that is CSN and DGN, respectively. 15 Selective electrical stimulation of each sensory branch revealed that reflex excitation of the bladder required different stimulation frequencies and was mediated by spinal (DGN) or supraspinal (CSN) networks. 10 We translated these preclinical findings to a cohort of patients with chronic SCI. We measured changes in bladder pressure and perineal muscle activity in response to IU stimulation of the proximal and distal urethral segments, corresponding to CSN and DGN components of the pudendal nerve, respectively. In contrast to observations in acute spinalized cats, 10 electrical stimulation of CSN and DGN afferents revealed that excitatory pudendal-tobladder reflex pathways remained intact in individuals with SCI. METHODS We measured responses of the bladder and striated perineal muscle to selective IU electrical stimulation in 7 participants with chronic SCI. Experimental protocols were approved by the Duke University Medical Center institutional review board and all participants provided written informed consent. Study inclusion criteria included neurologically stable SCI greater than 1 year after injury at or above T12, neurogenic bladder confirmed by cystometry and absent potential confounding factors, eg urethral stricture/obstruction or urinary tract infection. Experimental Setup Instrumentation in each participant included urethral insertion of a 12Fr Bardex Foley catheter to adjust bladder volume and a 4Fr BPC-4L polyvinylchloride catheter to measure bladder pressure as well as rectal insertion of a 9Fr RPC-9 balloon catheter (Life-Tech, Stafford, Texas) to measure abdominal pressure. The latter 2 catheters were connected in series with Deltran I pressure transducers. EMG activity of the transverse perineal muscles was recorded by pairs of 1512A-M stainless steel wires (Life- Tech) inserted percutaneously through the perineum. Pressure and EMG signals were filtered (direct current to 40 Hz, 3 to 1 khz), amplified (gain 1,000) with an ETH-255 device (iworx/cb Sciences, Dover, New Hampshire) and sampled digitally at 5 khz on a computer. Baseline Bladder Function Measurement At the start of each experiment P det, defined as bladder pressure minus abdominal pressure, and perineal EMG activity were measured as the bladder was filled with room temperature saline at 20 to 40 ml per minute (fig. 1). Bladder capacity (V th ) was defined as DE bladder activity with P det exceeding 30 cm H 2 O for at least 10 seconds. Infusion was discontinued if fluid leaked around the urethral catheter, signs of dysreflexia were visible or maximum limit (500 ml) was attained. IU Stimulation Instrumentation We inserted an 8 electrode stimulating catheter (diameter 1.4 mm, electrode length 3 mm and interelectrode separation 7 mm) in the urethra. In males with a mean SD urethral length of cm the active electrode was positioned 4 to 6 cm distal to the bladder neck to stimulate the proximal urethra and 3 to 5 cm proximal to the urethral meatus to stimulate the distal urethra. In the female participant the active electrode was positioned 1 cm distal to the bladder neck (proximal urethra) and 1 cm proximal to the urethral meatus (distal urethra). A single Empi 5000 return electrode, which was a inch rectangle, was placed on the upper hip. The electrodes were connected to a battery powered Empi 300PV electrical stimulator that delivered charge balanced asymmetric biphasic current pulses with a pulse width of 200 s. With the bladder empty the T to elicit a pudendal-topudendal reflex (BCR) was measured by increasing the amplitude of current pulses delivered at 2 Hz until a triggered EMG response or anal twitch was observed (see table). Tp and Td were measured individually at stimulating contacts positioned in the proximal and distal urethra, respectively (see table). If no BCR was elicited, a default Tp or Td of 15 ma was used. Figure 1. Distention evoked bladder contraction during initial urodynamic fill confirmed intact detrusor muscle and pelvic nerve function. Recorded perineal electromyogram (raw EMG) was rectified and averaged to determine maximum EMG activity (MA EMG) evoked during sustained bladder contraction. s, seconds.

3 PUDENDAL SENSORY PATHWAYS MODULATE BLADDER AND URETHRAL ACTIVITY 739 Participant data Pt 1 Pt 2 Pt 3 Pt 4 Pt 5 Pt 6 Pt 7 Age Gender M M M M M F M SCI: Yrs Level T12 T12 T6 T1 C5 T8 T8 Complete Yes Yes No No No Yes Yes Anticholinergics No No No Yes No No Yes BCR Yes No Yes Yes Yes Yes No V th (ml) DE P det (cm H 2 O) Electrical stimulation (cm H 2 O): Proximal Distal Tp (ma) Td (ma) Stimulation Protocol The bladder was filled to approximately 80% of V th,or500 ml if there was no DE bladder contraction. We applied 30-second trains of current pulses at multiples (2T and 4T) of the T current needed to evoke BCR. We performed a randomized sequence of 6 stimulation trials that combined 2 stimulus amplitudes (2 and 4 Tp or Td) and 3 frequencies (2, 10 and 35 Hz). In patients 1 and 4 additional stimulation trials (20 Hz and amplitude T to 4T) were done with the active electrode located at the bladder neck. Data Analysis The baseline bladder pressure was calculated as the P det averaged during 2 seconds before electrical stimulation. An evoked response was characterized by peak P det, normalized to the maximum P det measured during each initial urodynamic fill (fig. 1). An excitatory bladder response was defined as a minimum P det increase of 8 cm H 2 O above baseline during stimulation that was also at least a 10% increase in normalized P det. We calculated the mean perineal EMG activity evoked during each 30-second stimulus train by first removing the stimulus artifact (6-ms window) from the raw EMG and averaging over the stimulation duration. The effects of this blanking window on overall measured EMG activity was negligible, considering that 1) IU stimulation did not directly activate the recorded perineal muscle and 2) this window was briefer than the typical latency to evoke BCR activity. All EMG activity was normalized to the peak dyssynergic EMG activity evoked during each initial urodynamic fill (fig. 1). All data were averaged across multiple experiments and are expressed as the mean SE unless otherwise specified. Statistical analysis was done using 1-way ANOVA, followed by the Tukey multiple comparison test using S-PLUS. RESULTS Participants included 6 males and 1 female with a mean SD age of years (range 26 to 67). They were a mean of years (range 9 to 42) after injury. Injury level ranged from C5 to T12 and 4 participants were diagnosed with complete SCI. Two participants regularly used anticholinergic medication but stated that medication was discontinued at least 24 hours before the experiment. Urodynamics DE reflex bladder contractions were observed in 6 of 7 individuals during initial urodynamic fill. Spontaneous bladder and perineal activity was commonly observed below the DE contraction V th (fig. 1). V th for DE contractions (range 19 to 300 ml) and peak P det (range 34 to 113 cm H 2 O) varied highly among the 6 participants. Failure to evoke a DE bladder contraction in patient 7 suggested the possible residual effects of anticholinergic medication and this individual was excluded from further analysis (see table). Urethral-to-Perineal Reflex Electrical Activation With an empty bladder IU stimulation evoked reflex perineal EMG responses, ie the bulbocavernosus reflex, in 5 of 6 individuals (see table). The stimulation amplitude required to evoke this reflex was consistent in the proximal and distal urethral segments (mean and ma, respectively). Electrical stimulation did not elicit any apparent sensation other than a tapping sensation reported by patient 1. Reflex Bladder Activation by IU Stimulation At bladder volume greater than 80% of V th excitatory bladder responses were evoked in 4 of 6 participants by 30-second epochs of electrical stimulation applied to the proximal or distal urethra. Post-stimulus bladder contractions were noted in some trials but not considered responses to stimulation. The continued increase in P det beyond the end of the stimulation train indicated a possible stimulation evoked decrease in V th 16 or a triggered DE contraction. 17 Stimulation at different sites along the urethra resulted in qualitatively different bladder responses to

4 740 PUDENDAL SENSORY PATHWAYS MODULATE BLADDER AND URETHRAL ACTIVITY Figure 2. Distention and stimulation evoked bladder contractions and perineal EMG activity in individuals with spinal injury. Robust distention evoked bladder contractions were consistently accompanied by perineal musculature dyssynergic activity (A). Proximal IU stimulation at 10 Hz and 4T in patient 1 evoked sustained increases in P det and high perineal EMG activity that persisted throughout stimulation (B). Distal urethral electrical stimulation at 35 Hz and 2T in patient 1 elicited transient bladder contraction and low perineal EMG (C). IU stimulation. In 3 of 6 participants electrical stimulation of the proximal urethra evoked sustained bladder contraction with an average peak P det above baseline of cm H 2 O (range 17.6 to 52.9) (fig. 2, B). This corresponded to a normalized peak P det of cm H 2 O (range 0.16 to 0.53, fig. 3). This excitatory bladder response was elicited independently of spinal injury severity or a BCR response. In 3 of 6 participants electrical stimulation of the distal urethra evoked transient bladder contractions during the 30-second stimulus train (fig. 2, C). Figure 3. Peak magnitude of bladder contractions evoked by proximal and distal IU electrical stimulation (ES) in patients with SCI. Proximal urethral electrical stimulation evoked sustained bladder contraction in 3 of 6 individuals and distal urethral stimulation generated reflex bladder contractions in 3. In each group electrically evoked P det was significantly greater than nonresponses but there was no difference between proximal and distal IU stimulation (p 0.55). Norm, normalized. Asterisk indicates p Evoked contractions showed an average peak P det of cm H 2 O (range 9.3 to 40.9) with a corresponding normalized peak P det of cm H 2 O (range 0.2 to (fig. 3). Similar to proximal IU stimulation, the response was independent of a BCR response and spinal injury severity. Excitatory bladder responses were evoked at each site only in patient 1 (see table). Peak evoked P det depended on stimulation intensity during proximal but not distal IU stimulation (fig. 4, A). At each site evoked P det increased at higher stimulation frequencies but there was no statistical difference (p 0.27, fig. 4, B). In 2 experiments the feasibility of directly activating the bladder was tested by applying 30-second 20 Hz pulse trains at the most proximal electrode, ie the bladder neck (fig. 5, A). Instead of generating robust bladder contraction, as may be expected by direct activation of the pelvic nerve, responses were identical to those evoked by proximal IU stimulation (see table and fig. 5, A), that is a sustained bladder contraction (norm P det 0.41 cm) in patient 1 and no response in patient 4. Perineal EMG Activity Differential Modulation The level of perineal EMG activity measured during IU stimulation depended on the stimulation site and whether a bladder contraction was evoked. In contrast to the no stimulation condition (fig. 5, B), perineal EMG measured during no response trials increased significantly to approximately half the level of dyssynergic activity during initial urodynamic fill (fig. 5, B) at proximal (mean ) and distal (mean ) IU stimulation. However, in contrast to the further increase in perineal EMG activity during contractions generated by proximal urethral stimulation (mean ), the level of reflex

5 PUDENDAL SENSORY PATHWAYS MODULATE BLADDER AND URETHRAL ACTIVITY 741 Figure 4. Effect of stimulation (A) amplitude and (B) frequency on normalized (Norm) peak P det. Higher stimulus amplitudes applied to proximal urethra resulted in significantly larger P det (p 0.05). Contractions evoked by distal urethral stimulation were not sensitive to stimulus amplitude (p 0.33). Bladder contractions evoked by electrical stimulation of proximal (p 0.43) or distal (p 0.25) urethra did not depend on stimulation frequency (B). EMG activity during contraction trials evoked by distal urethral stimulation ( ) remained comparable to that in no response trials (fig. 5, B). Consistent with the reflex bladder contractions evoked by proximal IU stimulation, perineal EMG activity also depended on stimulation amplitude and frequency (fig. 6). In contrast, perineal EMG activity during distal IU stimulation showed no dependence on stimulation amplitude (p 0.33) or frequency (p 0.27). DISCUSSION These results bridge our current understanding of pudendal-to-bladder reflexes from cats to humans with chronic SCI. To our knowledge we report the first demonstration of bladder contraction evoked by electrical stimulation of the proximal or distal urethral segments in individuals with SCI. These results show a striking parallel to responses generated by CSN and DGN stimulation in the cat. 10 However, in contrast to cats, this study shows that proximal IU stimulation in humans with SCI can elicit sustained bladder contractions in the absence of supraspinal input. Concomitant measurement of perineal EMG activity during stimulation evoked bladder contractions revealed that efferent pudendal nerve activity depends on the stimulation site and on stimulation evoked bladder contraction. The activation of reflex bladder activity in individuals with complete or incomplete SCI indicated that these reflexes are mediated by spinal mechanisms. Bladder Contraction Evoked by Spinal Mechanism These results support the presence of a spinal mechanism, similar to that in cats, 5,10,18 which generates Figure 5. Electrical IU stimulation at bladder neck in 2 participants showed distention evoked bladder contractions (A). Stimulation trains of 30 seconds with 20 Hz frequency and T to 4T amplitude failed to evoke directly sustained bladder pressure increases comparable to distention evoked responses. Peak evoked P det in patients 1 (T 15 ma) and 4 (T 20 ma) was 41 and 4 cm H 2 O, respectively. Exp, patient. Reflex perineal EMG activity elicited by proximal and distal urethral electrical stimulation (ES) (B). Average normalized perineal EMG (Norm EMG) evoked during bladder contractions generated by proximal IU stimulation in 3 patients (1) was significantly greater than normalized EMG measured in distal IU stimulation evoked bladder contractions in 3 (4) and in stimulation trials with no bladder response (2 and 3). Asterisk indicates p Dagger indicates p

6 742 PUDENDAL SENSORY PATHWAYS MODULATE BLADDER AND URETHRAL ACTIVITY Figure 6. Normalized (Norm) perineal EMG evoked exhibited significant stimulation amplitude and frequency dependent changes during proximal IU stimulation. In contrast there was no significant effect of stimulation amplitude (p 0.33) or frequency (p 0.25) on evoked reflex EMG activity during distal IU stimulation. Asterisk indicates p reflex bladder contractions via the spinal convergence of pelvic and pudendal afferents. 1) Electrical activation of bladder contractions strongly depended on pelvic afferent activity and required a bladder volume of at least 80% of distention evoked V th. 2) As shown in the cat 12,19 and rat, 20 electrical activation of bladder contractions required stimulation amplitudes greater than or equal to the T needed to elicit a pudendal-topudendal reflex, ie BCR. This stimulation intensity suggests that the pudendal-to-bladder reflex in humans also involved the activation of smaller diameter myelinated fibers. 12 3) Finally, the dependence of response magnitude on stimulation frequency showed a pattern similar to that in cats. 9,10,21 Role of Pudendal Afferents The proximal urethra in the cat has a dual innervation pattern by branches of the pudendal nerve, where the CSN provides sensory innervation to the intraluminal surface and a perineal branch of the pudendal nerve provides mostly efferent input to the external urethral sphincter. 15 Although a CSN branch has not been identified in humans, 13,14 our results suggest that an analogous pudendal sensory branch innervates the proximal urethra. This would explain the requisite minimum bladder volume 12 and the absence of any change in the evoked bladder response between proximal IU and bladder neck stimulation at amplitudes and frequencies reported to elicit direct activation of parasympathetic fibers (fig. 5, A). 22,23 The role of putative CSN afferents in electrically evoked reflex bladder contraction is further supported by an excitatory urethrovesical reflex in humans, 24 which is mediated by sensory fibers innervating the proximal (or prostatic) urethra. 25 Our results extend previous knowledge of this reflex 11 to include the sustained reflex bladder contractions that occurred during each stimulation trial. Electrical stimulation of the distal urethra also evoked robust bladder contraction in 3 of 6 participants. The duration of these evoked responses was notably longer than the transient responses evoked by percutaneous stimulation of the pudendal nerve trunk, 26 which likely co-activated bladder inhibitory reflexes mediated by the tibial nerve or anal nerve afferents. 27,28 Despite these excitatory responses the clinical usefulness of distal IU stimulation in individuals with SCI may be tempered by the robust bladder inhibitory effects of DGN afferents. 6,8 This confounding effect was reflected by the comparatively smaller bladder response evoked at frequencies of 10 Hz or less (fig. 4, B). The clinical translation of this DGN pathway may also be limited by the absence in humans of the neonatal reflex, 29 which is an excitatory bladder reflex evoked by perigenital stimulation in cats. This physiological difference may explain the discrepancy between the DGN mediated bladder contractions evoked in this study and those in the cat. 5 Stimulation Site Effect on Reflex Perineal EMG Detrusor-sphincter dyssynergia remains a significant obstacle to restoring micturition in individuals with SCI and electrical stimulation of the pudendal nerve may exacerbate this condition. Given the absence of any flow or distention related urethral afferent activity during bladder contraction, ie isovolumetric bladder contraction, it was possible to identify the influence of the different sensory pathways on the reflex activation of perineal muscles. Stimulation of the proximal and distal urethra that failed to evoke bladder contraction (no response) revealed EMG activity associated with the guarding and bulbocavernosus reflexes, respectively. While bladder contractions evoked by proximal IU stimulation appeared to exacerbate the dyssynergic effects of pelvic afferents sensitive to changes in bladder pressure, 30 the decreased perineal EMG activity during bladder contraction evoked by distal IU stimulation suggests a potential inhibitory mechanism

7 PUDENDAL SENSORY PATHWAYS MODULATE BLADDER AND URETHRAL ACTIVITY 743 that may suppress dyssynergic activity (fig. 3). Further study to understand this mechanism may provide a clinical tool to achieve efficient micturition. Study Limitation: Intra-Individual Variability There were no definitive physical (eg gender or SCI level) or physiological (eg BCR) attributes predicted whether a participant would respond to proximal or distal urethral stimulation. Based on the consistent presence of an excitatory urethrovesical reflex in healthy humans 24 this variability in evoked bladder responses may be a result of plastic changes in spinal cord circuitry after injury. This is particularly relevant to the excitatory bladder responses evoked by distal IU stimulation since the dominant response to electrical stimulation of genital afferents is reflex inhibition of the bladder. In conclusion, the precise factor(s) underlying this variable pattern of reflex bladder contraction remains to be identified. ACKNOWLEDGMENTS Jean Maynor, John Beaudry and Betty O Neal assisted with the experiments. REFERENCES 1. Benevento BT and Sipski ML: Neurogenic bladder, neurogenic bowel, and sexual dysfunction in people with spinal cord injury. Phys Ther 2002; 82: de Groat WC, Araki I, Vizzard MA et al: Developmental and injury induced plasticity in the micturition reflex pathway. Behav Brain Res 1998; 92: Shingleton WB and Bodner DR: The development of urologic complications in relationship to bladder pressure in spinal cord injured patients. J Am Paraplegia Soc 1993; 16: Tai C, Wang J, Wang X et al: Bladder inhibition or voiding induced by pudendal nerve stimulation in chronic spinal cord injured cats. Neurourol Urodyn 2007; 26: Woock JP, Yoo PB and Grill WM: Activation and inhibition of the micturition reflex by penile afferents in the cat. 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