Hypothesis / aims of study
Detrusor external sphincter dyssynergia (DESD) is a major pathophysiological problem inducing lower urinary tract dysfunction (LUTD) in spinal cord injury (SCI) patients, which induces high-pressure voiding with increased residual urine volume that often necessitates bladder catheterization. Spinal neuronal networks controlling the interaction between the bladder and the external urethral sphincter (EUS) have been investigated to develop new treatments for DESD. The lumbar spinal coordinating center (LSCC) located in the L3/L4 spinal segments is known to have a role in bladder-EUS coordination. [1] While animal studies suggest the possibility of improving bladder function through L3 spinal cord stimulation [2, 3], the functional role of LSCC in treating LUTD in SCI remains unclear. Thus, we aimed to assess the effects of electrical stimulation of the L3/L4 spinal cord for LUTD in male mice with SCI.
Study design, materials and methods
Male C57BL/6 mice were used, and SCI mice underwent spinal cord transection at the T8-10 level. In 4-weeks SCI and spinal intact (SI) mice, two stainless steel wires were placed over the dorsal epidural surface of the L3/L4 spinal cord after laminectomy for electrical spinal cord stimulation (SCS) under isoflurane anesthesia. Then, we conducted awake cystometrograms (CMG) and EUS-electromyography (EMG) after recovery from the anesthesia. SCS of 0.1-0.2 ms duration at 2-4Hz was applied to the L3-L4 spinal cord for 8-10 seconds, which was initiated at the time when intravesical pressure of voiding bladder contractions started rising. The electrical stimulation intensity of SCS (3-4V) was set at 1 to 1.5-fold of the threshold intensity triggering body movement and adjusted to minimize it. CMG parameters such as the ratio of voided volume to bladder filling volume, residual urine volume (RU), micturition pressure, intercontraction interval (ICI), nonvoiding contraction (NVC) number/minute, and EMG parameters such as the ratio of active phase (AP) to silent phase (SP) of EUS bursting were measured before, during and after SCS.
Results
Seven SI mice and twenty-seven SCI mice were analyzed by simultaneous CMG and EUS-EMG recordings.
In comparison of CMG parameters before and after SCS, SI mice did not show significant differences in the ratio of voided volume to bladder filling volume (0.803 ± 0.308 vs. 0.858 ± 0.135, P = 0.875), micturition pressure (24.69 ± 6.63 vs. 25.29 ± 6.49, P = 0.999), or ICI (2.19 ± 0.49 vs. 1.99 ± 0.55, P = 0.375). However, in SCI mice, the ratio of voided volume to bladder filling volume after SCS was significantly higher than those before SCS. (0.415 ± 0.209 vs. 0.283 ± 0.193, P <0.001). Also, the NVC number/min (1.88 ± 0.48 vs. 2.05 ± 0.52, P = 0.017) and ICI (30.22 ± 16.47 vs. 33.82 ± 14.93, P = 0.007) in SCI mice after SCS were significantly lower than those before SCS.
In comparison of EUS-EMG parameters, SI mice after SCS did not show significant differences in the ratio of AP to SP compared with those before SCS (0.223 ± 0.053 vs. 0.232 ± 0.052, P = 0.578). However, in SCI mice after SCS, the ratio of AP to SP, which was increased after SCI vs. SI mice, was significantly lower than those before SCS (0.922 ± 0.316 vs. 1.252 ± 0.389, P <0.001) (Fig. 1).
Interpretation of results
No CMG or EUS-EMG parameters were altered after SCS in male SI mice, indicating that SCS with the stimulation intensity used in this study did not impact on lower urinary tract function under the normal condition.
However, in male SCI mice, detrusor overactivity evident as the number of NVC during the storage phase, which was increased after SCI, was decreased significantly after SCS, implying that SCS onto the L3/4 spinal cord could improve the storage dysfunction in SCI.
In addition, male SCI mice exhibited inefficient voiding with DESD, evident as the low ratio of voided volume to bladder filling volume and the high AP to SP ratio after SCI vs. SI mice. Then, SCS in SCI mice improved these voiding parameters, suggesting that SCS onto the L3/4 spinal cord could increase the EUS relaxation time during voiding to improve DESD, leading to higher voiding efficiency compared with the parameters before SCS. These results suggest that inadequate signal transduction in the LSCC located at the L3/L4 spinal cord can be restored by SCS to improve the voiding dysfunction due to DESD in SCI