This is the first indirect evidence of the presence of the LSCC in Humans. Neurogenic bladder dysfunction is a common sequela following spinal cord injury (SCI). Urological deficits after SCI manifest as detrusor hyperreflexia, detrusor sphincter dyssynergia (DSD), decreased compliance and loss of continence, requiring lifelong management, maintenance, and health care visits.  The disconnection between the pontine micturition center (PMC) and the lumbosacral centers controlling the lower urinary tract (LUT) is the responsible for the appearance DSD. Rats and pigs had been widely used as model for the study of the lower urinary tract. Nevertheless, the differences on the contractile activity of the external urethral sphincter during the micturition between those spices and humans had been historically used as the principal argument to criticize the value of those models on the translational aspect. The main difference between Rats, pigs and human beings lies on intermittent activation of the external urethral sphincter (EUS) during all the emptying phase of micturition in rats and during the last third of the same period in pigs meanwhile, the human EUS remains inactive during the voiding. The aim of this study was to explore and evaluate bladder function in the lower urinary tract (LUT) under normal conditions and after SCI in Human beings, Yucatan mini-pigs and rats performing urodynamic studies under fully awake/ conditions yields similar characteristics that are present in all urinary cycle phases found in human studies for both non-injured and post-injury conditions.

All animal procedures were performed according to the NIH Guide for the Care and Use of Laboratory animals. All protocols were reviewed and approved by the Institutional Animal Care and  Use Committee. For humans All procedures were conducted in compliance with National Institutes of Health guidelines. Study protocols were reviewed and approved by the local institutional review board committee. Urodynamics was conducted in awake female Yucatan minipigs (n=5) and male Wistar rats (n=5) prior to and at week 12 (W12) post T10/T11 severe contusion SCI. Additionally it were analyzed the urodynamic records of males under normal conditions (n=3) and after SCI (n=3).   Prior to the injury, the pigs were acclimated to being suspended in a sling in a still position. In order to evaluate bladder function, a double lumen catheter with a solid pressure sensor on the tip was inserted into the urinary bladder through the urethra for measuring intra-vesical pressure. A second pressure sensor was placed in the rectum to measure intra-abdominal pressure. At the same time, two perineal surface electrodes were anatomically placed to record the EMG activity. A weight flowmeter was used to perform flowmetry. All sensors were connected to urodynamic equipment (Laborie Aquarius® XT, NH, USA). Under isoflurane anesthesia, a PE-60 catheter was placed on the dome of the bladder as well as two needle electrodes were connected into the external urethral sphincter aimed to perform cystometrogram-electromyogram under fully awake conditions (2 hours after urethane recovery). The urodynamic studies were performed in accordance with the ICS protocols. The bladder capacity, filling pressure, voided volume, voiding efficiency, voiding pressure, electromyographic pattern, flow rate and voiding duration were recorded. Pre/post-injury data were compared qualitatively between species.

In rats, preinjury urodynamics shows an  initial  rise  in  intra-vesical  pressure (Pves) generated  by  the  detrusor's  contraction  under  isovolumetric  conditions,  an  emptying  phase  identified  by  phasic  contractions  of  the  external  urethral  sphincter  (EUS) which provokes sudden and rhythmic Pves increases known  as  high  frequency  pressure  oscillations  (HFPO)  with  concurrent  loss  of  pressure  during  the  expulsion  of  urine (which generates a plateau shape in the Pves record), and a third phase characterized by a Pves increase known as rebound. Similar pattern was found after SCI. In the pig, during the preinjury urodynamics, two different flow patterns were noted. Pattern one was characterized by a continuous bell-shaped curve with slight to moderate right asymmetry of the bell matching with very low EUS EMG activity. The second flow pattern showed similar characteristics except that during the last third of the contraction curve, a rhythmic intermittence of the flow occurred accompanied by a bursting-like firing of the EUS. Moreover, it was found that urodynamic data were consistent with overflow incontinence, detrusor instability, detrusor underactivity and detrusor-sphincter dyssynergia type 1, 2, and 3. In healthy humans a continuous bell-shaped contractile curve during void accompanied by very low EMG activity and continuous urine flow were found wile a typical pattern of DSD type 2 were found in SCI patients.

RESULTS Performing urodynamic studies under fully awake/ conditions showed the differences of EUS activity during the voiding in humans (silent) compared with rats and pigs (intermittent). The existence of a lumbar spinal coordinating center (LSCC) at L3-L4 spinal level had been proved in rats as responsible for the intermittent bursting pattern of the EUS in rats making possible the existence of a similar structure in pigs. After SCI all species showed EUS intermittency suggesting the presence of comparable neural circuitries between rats pigs and human remaining under the level of injury, including corresponding plasticity and pathologic processes after SCI. We hypothesized the existence in humans of a structure similar to the LSCC which become silent after toileting training which becomes active after SCI and this structure is responsible for the DSD type 2.

This result shows that the use of different species models for the study of the LUT offers a unique perspective on the functional aspect. Also the first indirect evidence of the presence of the LSCC opens a new window for the comprehension of the LUT and a new possible target for the treatment of the LUT dysfunction.