Most human spinal cord injuries are anatomically incomplete, leaving some fibers still connecting the brain with the sublesional spinal cord. Spared descending fibers of the brainstem motor control system can be activated by deep brain stimulation (DBS) of the cuneiform nucleus (CnF), a subnucleus of the mesencephalic locomotor region (MLR). The MLR is an evolutionarily highly conserved structure which initiates and controls locomotion in all vertebrates. Acute electrical stimulation experiments in female adult rats with incomplete spinal cord injury conducted in our lab showed that CnF-DBS was able to re-establish a high degree of locomotion five weeks after injury, even in animals with initially very severe functional deficits and white matter lesions up to 80-95%. Here, we analyzed whether CnF-DBS can be used to support medium-intensity locomotor training and long-term recovery in rats with large but incomplete spinal cord injuries. Rats underwent rehabilitative training sessions three times per week in an enriched environment, either with or without CnF-DBS supported hindlimb stepping. After 4 weeks, animals that trained under CnF-DBS showed a higher level of locomotor performance than rats that trained comparable distances under non-stimulated conditions. The MLR does not project to the spinal cord directly; one of its main output targets is the gigantocellular reticular nucleus in the medulla oblongata. Long-term electrical stimulation of spared reticulospinal fibers after incomplete spinal cord injury via the CnF could enhance reticulospinal anatomical rearrangement and in this way lead to persistent improvement of motor function. By analyzing the spared, BDA-labeled giganto-spinal fibers we found that their gray matter arborization density after discontinuation of CnF-DBS enhanced training was lower in the lumbar L2 and L5 spinal cord in stimulated as compared to unstimulated animals, suggesting improved pruning with stimulation-enhanced training. An on-going clinical study in chronic paraplegic patients investigates the effects of CnF-DBS on locomotor capacity.
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- Martin E Schwab
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Neurogenic lower urinary tract dysfunction typically develops after spinal cord injury. We investigated the time course and the anatomical changes in the spinal cord that may be causing lower urinary tract symptoms following injury. Rats were implanted with a bladder catheter and external urethral sphincter electromyography electrodes. Animals underwent a large, incomplete spinal transection at the T8/9 spinal level. At 1, 2-3, and 4 weeks after injury, the animals underwent urodynamic investigations. Urodynamic investigations showed detrusor overactivity and detrusor-sphincter-dyssynergia appearing over time at 3-4 weeks after injury. Lower urinary tract dysfunction was accompanied by an increase in density of C-fiber afferents in the lumbosacral dorsal horn. CRF-positive Barrington's and 5-HT-positive bulbospinal projections drastically decreased after injury, with partial compensation for the CRF fibers at 3-4 weeks. Interestingly, a decrease over time was observed in the number of GABAergic neurons in the lumbosacral dorsal horn and lamina X, and a decrease of glutamatergic cells in the dorsal horn. Detrusor overactivity and detrusor-sphincter-dyssynergia might therefore arise from a discrepancy in inhibitory/excitatory interneuron activity in the lumbosacral cord as well as input changes which develop over time after injury. The processes point to spinal plastic changes leading to malfunction of the important physiological pathway of lower urinary tract control.
BACKGROUND: Deep brain stimulation (DBS) has clear beneficial effects on motor signs in movement disorders, but much less is known about its impact on lower urinary tract (LUT) function.
OBJECTIVE: To evaluate the effects of DBS on LUT function in patients affected by movement disorders.
DESIGN, SETTING, AND PARTICIPANTS: We prospectively enrolled 58 neurological patients affected by movement disorders, who were planned to receive DBS.
INTERVENTION: DBS in the globus pallidus internus, ventral intermediate nucleus of the thalamus, or subthalamic nucleus.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Subjective symptom questionnaires (International Prostate Symptom Score) and objective urodynamic studies were carried out before implantation of the DBS leads and several months after surgery. After DBS surgery, urodynamic investigations were performed with DBS ON as well as DBS OFF.
RESULTS AND LIMITATIONS: We enrolled patients suffering from Parkinson's disease (n = 39), dystonia (n = 11), essential tremor (n = 5), Holmes tremor (n = 2), and multiple sclerosis with tremor (n = 1). DBS of the globus pallidus internus resulted in worsening of LUT symptoms in 25% (four of 16) of the cases. DBS of the subthalamic nucleus in patients with Parkinson's disease led to normalization of LUT function in almost 20% (six of 31 patients), while a deterioration was seen in only one (3%) patient. DBS of the ventral intermediate nucleus of the thalamus improved LUT function in two (18%) and deteriorated it in one (9%) patient with tremor.
CONCLUSIONS: DBS effects on LUT varied with stimulation location, highly warranting patient counseling prior to DBS surgery. However, more well-designed, large-volume studies are needed to confirm our findings.
PATIENT SUMMARY: In this report, we looked at outcomes of deep brain stimulation on lower urinary tract function. We found that outcomes varied with stimulation location, concluding that counseling of patients about the effects on lower urinary tract function is highly recommended prior to surgery.
Despite the fact that a majority of patients with an injury to the spinal cord develop lower urinary tract dysfunction, only few treatment options are available currently once the dysfunction arises. Tibial nerve stimulation has been used in pilot clinical trials, with some promising results. Hence, we investigated whether the early application of transcutaneous tibial nerve stimulation in the animal model of spinal cord injured rats can prevent the development of detrusor overactivity and/or detrusor-sphincter-dyssynergia. Rats were implanted with a bladder catheter and external urethral sphincter electromyography electrodes. A dorsal over-hemisection, resulting in an incomplete spinal cord injury at the T8/9 spinal level, induced immediate bladder paralysis. One week later, the animals received daily tibial nerve or sham stimulation for 15 days. Effects of stimulation on the lower urinary tract function were assessed by urodynamic investigation. Measurements showed improvements of several key parameters of lower urinary tract function-in particular, non-voiding bladder contractions and intravesical pressure-immediately after the completion of the stimulation period in the stimulated animals. These differences extinguished one week later, however. In the dorsal horn of the lumbosacral spinal cord, a small significant increase of the density of C-fiber afferents layers I-II was found in the stimulated animals at four weeks after spinal cord injury. Tibial nerve stimulation applied acutely after spinal cord injury in rats had an immediate beneficial effect on lower urinary tract dysfunction; however, the effect was transitory and did not last over time. To achieve more sustainable, longer lasting effects, further studies are needed looking into different stimulation protocols using optimized stimulation parameters, timing, and treatment schedules.
Lower urinary tract dysfunction affects a multitude of patients. Current therapeutic approaches are limited and very little is known about the mechanisms in failure of bladder control. Thus, more basic research is clearly needed to elucidate the underlying pathological mechanisms and to develop novel treatment strategies in urology. Noninvasive tests such as the void-spot assay and the metabolic cage and more invasive urodynamics investigations are currently used to assess lower urinary tract function in animals, in particular rodents. The noninvasive tests give some insights into the functionality of the system, whereas urodynamics testing yields an objective evaluation that allows distinction of different pathologies and investigations of the underlying neuronal malfunctions. PATIENT SUMMARY: We briefly summarize methods currently used to assess impairments of bladder function in animal models. Both noninvasive and invasive methods are available and can be used to understand and improve human health. An accurate and detailed diagnosis is, however, possible only with urodynamics assessments.
BACKGROUND: Ultrasound is generally used to measure postvoid residual (PVR) in daily clinical practice for a basic assessment of voiding dysfunction. In animal research, however, PVR is measured mostly by expelling the urine with gentle squeezing of the bladder.
OBJECTIVE: To assess the translational value of measuring PVR by ultrasound in awake rats with the aim of obtaining directly comparable data sets in patients and rodent models.
DESIGN, SETTING, AND PARTICIPANTS: A prospective animal study was conducted in 10 rats with large, incomplete thoracic spinal cord injury resulting in severe bladder impairment. Lower urinary tract function was assessed by urodynamics with implanted bladder catheter and external urethral sphincter electrodes, allowing for repeated measurements over time. Immediately after the last micturition cycle in the urodynamic investigation, PVR was first assessed by ultrasound using a 7.5 MHz linear probe and then by manually expelling the urine via gentle pressure on the abdomen.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: PVR was measured by ultrasound and by manually expelling the urine. Paired t test was used to analyze the difference between the two measurements 1 and 2 wk after spinal cord injury.
RESULTS AND LIMITATIONS: PVR assessed by ultrasound was equal to and not statistically different from the volumes obtained by manual expulsion in intact rats, both before injury and during the first 2 wk after spinal cord injury (intact: 0.16 ± 0.07 vs 0.14 ± 0.09 ml, p = 0.08; week 1: 1.67 ± 0.53 vs 1.71 ± 0.55 ml, p = 0.67; week 2: 1.16 ± 0.35 vs 0.98 ± 0.43 ml, p = 0.11). The main limitation of ultrasound for measuring PVR is the restricted availability of ultrasound machines in animal research laboratories.
CONCLUSIONS: Ultrasound is a valuable translational tool to measure PVR in awake rats reflecting the situation in humans.
PATIENT SUMMARY: We measured postvoid residual by ultrasound in awake rats, analogous to clinical examination in humans. Ultrasonography provided similar values to the generally used manual bladder expulsion.
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Severe spinal cord injuries result in permanent paraparesis in spite of the frequent sparing of small portions of white matter. Spared fibre tracts are often incapable of maintaining and modulating the activity of lower spinal motor centres. Effects of rehabilitative training thus remain limited. Here, we activated spared descending brainstem fibres by electrical deep brain stimulation of the cuneiform nucleus of the mesencephalic locomotor region, the main control centre for locomotion in the brainstem, in adult female Lewis rats. We show that deep brain stimulation of the cuneiform nucleus enhances the weak remaining motor drive in highly paraparetic rats with severe, incomplete spinal cord injuries and enables high-intensity locomotor training. Stimulation of the cuneiform nucleus during rehabilitative aquatraining after subchronic (n = 8 stimulated versus n = 7 unstimulated versus n = 7 untrained rats) and chronic (n = 14 stimulated versus n = 9 unstimulated versus n = 9 untrained rats) spinal cord injury re-established substantial locomotion and improved long-term recovery of motor function. We additionally identified a safety window of stimulation parameters ensuring context-specific locomotor control in intact rats (n = 18) and illustrate the importance of timing of treatment initiation after spinal cord injury (n = 14). This study highlights stimulation of the cuneiform nucleus as a highly promising therapeutic strategy to enhance motor recovery after subchronic and chronic incomplete spinal cord injury with direct clinical applicability.