Video_1_Non-invasive Neuromodulation of Spinal Cord Restores Lower Urinary Tract Function After Paralysis.MP4

<p>It is commonly assumed that restoration of locomotion is the ultimate goal after spinal cord injury (SCI). However, lower urinary tract (LUT) dysfunction is universal among SCI patients and significantly impacts their health and quality of life. Micturition is a neurologically complex behavior that depends on intact sensory and motor innervation. SCI disrupts both motor and sensory function and leads to marked abnormalities in urine storage and emptying. Current therapies for LUT dysfunction after SCI focus on preventing complications and managing symptoms rather than restoring function. In this study, we demonstrate that Transcutaneous Electrical Spinal Stimulation for LUT functional Augmentation (TESSLA), a non-invasive neuromodulatory technique, can reengage the spinal circuits' active in LUT function and normalize bladder and urethral sphincter function in individuals with SCI. Specifically, TESSLA reduced detrusor overactivity (DO), decreased detrusor-sphincter dyssynergia (DSD), increased bladder capacity and enabled voiding. TESSLA may represent a novel approach to transform the intrinsic spinal networks to a more functionally physiological state. Each of these features has significant clinical implications. Improvement and restoration of LUT function after SCI stand to significantly benefit patients by improving their quality of life and reducing the risk of incontinence, kidney injury and urinary tract infection, all the while lowering healthcare costs.</p

Interaction between locomotion and bladder circuits.

<p>(A) Representative EMG recordings from the soleus and tibialis anterior (TA) muscles from a spinal rat suspended in a harness and stepping bipedally on a treadmill at 13.5 cm/s under the influence of eEmc (40 Hz between L2 and S1). The rat begins to micturate at the beginning of the green shaded area. Note the shorter step cycle periods and higher EMG amplitudes a few steps prior to (red shaded area) and during (green shaded area) micturition. (B) EMG amplitude distribution plots showing an increase in the amount of co-activation of the soleus and TA muscles during the steps immediately before and during micturition. The red and green bars above the distribution plots correspond to the shaded regions in (A). (C) Step cycle duration and soleus and TA integrated EMG (iEMG) for each step shown in (A). (D) Mean (±SEM) step cycle duration and soleus and TA EMG burst durations for the regions highlighted in (A). Representative EMG recordings from the soleus and TA muscles when the rat hindlimbs were suspended above the treadmill belt (unloaded) during saline infusion (1 cc) into the bladder via a urethral catheter (E) or during 40 Hz eEmc (F).</p

Voiding efficiency with eEmc.

<p>Mean (±SEM, n = 6 rats, 3 trials each rat) total percent volume voided in the first 90 sec after the initiation of eEmc at different frequencies after infusion of 1cc of saline via a urethral catheter in spinal rats with the hindlimbs suspended above a treadmill belt. In addition, the volume of saline voided within 30 sec after the 40-Hz stimulation was stopped (post-eEmc) is shown. *, significantly different from 1 Hz at <i>P</i><0.05.</p

Initiation of Bladder Voiding with Epidural Stimulation in Paralyzed, Step Trained Rats

<div><p>The inability to control timely bladder emptying is one of the most serious challenges among the several functional deficits that occur after a complete spinal cord injury. Having demonstrated that electrodes placed epidurally on the dorsum of the spinal cord can be used in animals and humans to recover postural and locomotor function after complete paralysis, we hypothesized that a similar approach could be used to recover bladder function after paralysis. Also knowing that posture and locomotion can be initiated immediately with a specific frequency-dependent stimulation pattern and that with repeated stimulation-training sessions these functions can improve even further, we reasoned that the same two strategies could be used to regain bladder function. Recent evidence suggests that rats with severe paralysis can be rehabilitated with a multisystem neuroprosthetic training regime that counteracts the development of neurogenic bladder dysfunction. No data regarding the acute effects of locomotion on bladder function, however, were reported. In this study we show that enabling of locomotor-related spinal neuronal circuits by epidural stimulation also influences neural networks controlling bladder function and can play a vital role in recovering bladder function after complete paralysis. We have identified specific spinal cord stimulation parameters that initiate bladder emptying within seconds of the initiation of epidural stimulation. The clinical implications of these results are substantial in that this strategy could have a major impact in improving the quality of life and longevity of patients while simultaneously dramatically reducing ongoing health maintenance after a spinal cord injury.</p></div

Hindlimb evoked potentials varying with eEmc and bladder voiding.

<p>(A) Mean evoked potentials (n = 4 rats, 10 potentials for each condition/rat) from the TA and soleus muscles under the influence of eEmc at 1 Hz between L2 and S1 during voiding and not voiding with a filled bladder in a spinal rat with its hindlimbs suspended above a treadmill belt. (B) Mean evoked potentials (n = 7 rats, 10 potentials for each condition/rat) in the soleus and TA induced by eEmc at 1, 5, and 40 Hz. Significant differences (<i>P</i><0.05) in evoked potential amplitudes in the absence of voiding: TA - black < blue < red; Soleus - blue < red < black.</p

Total average volume of urine voided manually daily.

<p>Mean (±SEM) total daily volume of urine voided by manual bladder expression in spinal rats trained to step bipedally on a treadmill at 13.5 cm/s beginning 7 days post-surgery or in untrained rats (n = 3 rats/group). *, significant difference between trained and untrained at <i>P</i><0.05.</p

Changes in EUS activity with and without eEmc.

<p>(A) A representative EMG recording from the EUS muscle during infusion of 1 cc of saline into the bladder (orange highlight) and during voiding under the influence of 1 Hz eEmc (green highlight). (B) Average (20 potentials) evoked potentials recorded from the EUS muscle of a spinal rat at 1-Hz stimulation when the bladder was empty, filled, or voiding.</p