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We have learned that micturition is comprised of two basic phases: storage and emptying; during bladder emptying, the pontine and periaqueductal gray (PAG) micturition center ensures coordinated inhibition of striated sphincter and pelvic floor muscles and relaxation of the internal urethral sphincter while the detrusor muscle contracts. Due to several disorders of the brain and spinal cord, the achieved voluntary control of bladder function can be impaired, and involuntary mechanisms of bladder activation again become evident. However, little has been discovered so far how higher brain centers strictly regulate the intricate process of micturition. The present functional magnetic resonance imaging (fMRI) study attempted to identify brain areas involved in such voluntary control of the micturition reflex by performing functional magnetic resonance imaging during a block design experiment in 12 healthy subjects. The protocol consisted of alternating periods of rest and pelvic muscle contraction during empty-bladder condition (EBC) and full-bladder condition (FBC). Repeated pelvic floor muscle contractions were performed during full bladder to induce a stronger contrast of bladder sensation, desire to void and inhibition of the micturition reflex triggering, since the subjects were asked not to urinate. Empty-bladder conditions were applied as control groups. Activation maps calculated by contrast of subtracting the two different conditions were purposed to disclose these brain areas that are involved during the inhibition of the micturition reflex, in which contrast, the SMA, bilateral putamen, right parietal cortex, right limbic system, and right cerebellum were found activated. The combined activation of basal ganglia, parietal cortex, limbic system, and cerebellum might support the assumption that a complex visceral sensory–motor program is involved during the inhibitory control of the micturition reflex.

Spinal cord injury leads to severe locomotor deficits or even complete leg paralysis. Here we introduce targeted spinal cord stimulation neurotechnologies that enabled voluntary control of walking in individuals who had sustained a spinal cord injury more than four years ago and presented with permanent motor deficits or complete paralysis despite extensive rehabilitation. Using an implanted pulse generator with real-time triggering capabilities, we delivered trains of spatially selective stimulation to the lumbosacral spinal cord with timing that coincided with the intended movement. Within one week, this spatiotemporal stimulation had re-established adaptive control of paralysed muscles during overground walking. Locomotor performance improved during rehabilitation. After a few months, participants regained voluntary control over previously paralysed muscles without stimulation and could walk or cycle in ecological settings during spatiotemporal stimulation. These results establish a technological framework for improving neurological recovery and supporting the activities of daily living after spinal cord injury. Spatially selective and temporally controlled stimulation of the spinal cord, together with rehabilitation, results in substantial restoration of locomotor function in humans with spinal cord injury.

We studied the central representation of pudendal afferents arising from the clitoral nerves in 15 healthy adult female subjects using electrical dorsal clitoral nerve stimulation and fMRI. As a control body region, we electrically stimulated the right hallux in eight subjects. In a block design experiment, we applied bilateral clitoral stimulation and unilateral (right) hallux stimulation. Activation maps were calculated for the contrasts ‘electrical dorsal clitoral nerve stimulation versus rest’ and ‘electrical hallux stimulation versus rest’. A random-effect group analysis for the clitoral stimulation showed significant activations bilateral in the superior and inferior frontal gyri, insulae and putamen and in the postcentral, precentral and inferior parietal gyri (including the primary and secondary somatosensory cortices). No activation was found on the mesial surface of the postcentral gyrus. For the hallux, activations occurred in a similar neuronal network but the activation in the primary somatosensory cortex was localized in the inter-hemispheric fissure. The results of this study demonstrate that the central representation of pudendal afferents arising from the clitoral nerves and sensory inputs from the hallux can be studied and distinguished from each other by fMRI. From the somatotopic order described in the somatosensory homunculus one would expect for electrical clitoral nerve stimulation activation of the mesial wall of the postcentral gyrus. In contrast, we found activations on the lateral surface of the postcentral gyrus.

Study design: Review by the spinal cord outcomes partnership endeavor (SCOPE), which is a broad-based international consortium of scientists and clinical researchers representing academic institutions, industry, government agencies, not-for-profit organizations and foundations. Objectives: Assessment of current and evolving tools for evaluating human spinal cord injury (SCI) outcomes for both clinical diagnosis and clinical research studies. Methods: a framework for the appraisal of evidence of metric properties was used to examine outcome tools or tests for accuracy, sensitivity, reliability and validity for human SCI. Results: Imaging, neurological, functional, autonomic, sexual health, bladder/bowel, pain and psychosocial tools were evaluated. Several specific tools for human SCI studies have or are being developed to allow the more accurate determination for a clinically meaningful benefit (improvement in functional outcome or quality of life) being achieved as a result of a therapeutic intervention. Conclusion: Significant progress has been made, but further validation studies are required to identify the most appropriate tools for specific targets in a human SCI study or clinical trial.

We investigated (i) the central representation of lower urinary tract (LUT) control and (ii–iii) the acute and short-term central neuromodulatory effect of peripheral pudendal nerve stimulation in incomplete spinal cord injured (SCI) patients using functional magnetic resonance imaging (fMRI). The urinary bladder of eight SCI patients has been passively filled and emptied using a catheter, to identify the neural substrate of bladder control (i), and with simultaneous peripheral pudendal nerve stimulation to investigate its acute central neuromodulatory effect (ii). To identify the potential effects of pudendal nerve stimulation treatment (iii), six patients underwent a 2-week training using pudendal nerve stimulation followed by another fMRI session of bladder filling. The pre- and post-training fMRI results have been compared and correlated with the patient's pre- and post-training urological status. Our results suggest that the central representation of bladder filling sensation is preserved in the subacute stage of incomplete SCI. However, compared to earlier data from healthy subjects, it shows decreased neural response in right prefrontal areas and increased in left prefrontal regions, indicating diminished inhibitory micturition control as well as, compensatory or decompensatory reorganization of bladder control. We also provide evidence for a neuromodulatory effect of acute pudendal nerve stimulation, which was most prominent in the right posterior insula, a brain region implicated in homeostatic interoception in human. Pudendal stimulation training also induced significant neuromodulation, predominantly signal increases, in the normal cortical network of bladder control. Correlations with the patient's urological status indicate that this neuromodulatory effect may reflect the clinical improvement following training.

Using functional magnetic resonance imaging (fMRI) we investigated the cortical and subcortical representations during bladder filling and the effect of simultaneous stimulation of the dorsal clitoral nerve on these cortical and subcortical structures. After approval of the local ethics committee, 8 healthy females were included. Prior to scanning, subjects were catheterized and the bladder was filled until first desire to void occurred. In a block design protocol we performed repetitive manual bladder filling (FILLING) and emptying of additional 80 ml saline, alternating with rest conditions (REST) of constant bladder volume. The protocol was repeated with simultaneous stimulation of the dorsal clitoral nerve during the filling periods (COMBINED). Activation maps were calculated by means for 3 different contrasts: 1) FILLING > REST, 2) COMBINED > REST and 3) FILLING > COMBINED. A group analysis of contrast 1) showed activation of the right prefrontal and orbitofrontal cortices, the insula bilaterally, the left precuneus, the parietal operculum bilaterally, the cerebellum bilaterally ( q(FDR) ≤ 0.001), the right anterior cingulate gyrus ( q(FDR) ≤ 0.005) and the right anterior mid pons ( q(FDR) ≤ 0.05). Contrast 2) showed activation in the right frontal area, the left insula, the parietal operculum bilaterally and the left cerebellum ( q(FDR) ≤ 0.001). Deactivations were found in the middle frontal gyrus bilaterally and the post- and paracentral gyri bilaterally. Contrast 3) revealed stronger activation during FILLING in the bilateral frontal and prefrontal areas, the right anterior cingulated gyrus, and the right putamen ( q(FDR) ≤ 0.05). Only the right insula showed stronger activation during the COMBINED condition. Simultaneous dorsal clitoral nerve stimulation during bladder filling reduced the activation of certain cortical areas suggesting a neuromodulatory effect of this stimulation on supraspinal centres involved in lower urinary tract control.

Purpose To investigate the potential effect of tolterodine on the human heart rate variability (HRV). Oral antimuscarinic treatment for overactive bladder might significantly alter HRV, which is an important predictor for cardiac and all-cause mortality. Yet, little information exists regarding the influence of oral antimuscarinics on the HRV. Methods Healthy female volunteers were randomly assigned to either placebo, tolterodine extended release (ER) 4 or 8 mg. Before and 4 h post treatment, a 10 min electrocardiogram (ECG) was recorded in supine position. Frequency domain and time domain analysis of both ECG measurements resulted in very low frequency (VLF), low frequency (LF), and high frequency (HF) data, the root mean square of differences of successive NN (= normal to normal, i.e. interval between two R-peaks) intervals (RMSSD), and the standard deviation of the NN intervals (SDNN). Results Thirty subjects (mean age: 23.7 ± 2.3 years) were investigated. Placebo caused no significant HRV changes. Tolterodine 4 mg significantly increased heart rate (HR) and significantly decreased VLF. Tolterodine 8 mg significantly decreased HF, VLF, RMSSD and SDNN and significantly increased HR and LF/HF ratio. The changes observed with 4 mg were not significantly different versus placebo, but 8 mg significantly increased LF/HF as compared to placebo. Conclusions A single dose of 8 mg tolterodine ER, but not 4 mg seems to reduce resting HRV versus placebo in young healthy subjects. This might be particular relevant for patients with pre-existing cardiac conditions on daily overactive bladder drug treatment and should be further investigated in larger trials.

To the Editor: Neurogenic urinary incontinence is most often due to detrusor hyperreflexia, and it is usually treated by partially blocking the efferent parasympathetic innervation to the detrusor muscle of the bladder with anticholinergic drugs. These drugs have troublesome side effects, however, and may not restore continence. Botulinum toxin A selectively blocks the release of acetylcholine from nerve endings and accordingly blocks neural transmission. We hypothesized that injections of botulinum toxin A into the detrusor muscle of the bladder might ameliorate detrusor hyperreflexia in patients with neurogenic incontinence by impairing parasympathetic nervous transmission. During the past year, we treated 21 . . .

Objectives Although botulinum neurotoxin type A (BoNT/A) intradetrusor injections are a recommended therapy for neurogenic detrusor overactivity (NDO), refractory to antimuscarinic drugs, a standardisation of injection technique is missing. Furthermore, some basic questions are still unanswered, as where the toxin solution exactly spreads after injection. Therefore, we investigated the distribution of the toxin solution after injection into the bladder wall, using magnet resonance imaging (MRI). Methods Six patients with NDO were recruited. Three of six patients received 300 U of BoNT/A + contrast agent distributed over 30 injection sites (group 1). The other three patients received 300 U of BoNT/A + contrast agent distributed over 10 injection sites (group 2). Immediately after injection, MRI of the pelvis was performed. The volume of the detrusor and the total volume of contrast medium inside and outside the bladder wall were calculated. Results In all patients, a small volume (mean 17.6%) was found at the lateral aspects of the bladder dome in the extraperitoneal fat tissue, whereas 82.4% of the injected volume reached the target area (detrusor). In both groups there was a similar distribution of the contrast medium in the target area. A mean of 33.3 and 25.3% of the total detrusor volume was covered in group 1 and 2, respectively. Six weeks after injection, five of six patients were continent and showed no detrusor overactivity in the urodynamic follow-up. No systemic side effects were observed. Conclusions Our results provide morphological arguments that the currently used injection techniques are appropriate and safe.

OBJECTIVES AND METHODS: To assess the impairment of supraspinal control over spinal sympathetic centres and the occurrence of autonomic dysreflexia in patients with spinal cord injury. Autonomic dysreflexia is caused by the disconnection of spinal sympathetic centres from supraspinal control and is characterised by paroxysmal hypertensive episodes caused by non-specific stimuli below the level of the lesion. Therefore, patients with spinal cord injury were examined clinically and by different techniques to assess the occurrence of autonomic dysreflexia and to relate disturbances of the sympathetic nervous system to episodes of autonomic dysreflexia. RESULTS: None of the paraplegic patients, but 59% (13/22) of tetraplegic patients (91% of the complete, 27% of the incomplete patients) presented signs of autonomic dysreflexia during urodynamic examination. Only 62% of the tetraplegic patients complained about symptoms of autonomic dysreflexia. Pathological sympathetic skin responses (SSRs) of the hands were related to signs of autonomic dysreflexia in 93% of cases. No patient with preserved SSR potentials of the hands and feet showed signs of autonomic dysreflexia, either clinically or during urodynamic examination. Ambulatory blood pressure measurements (ABPMs) indicated a loss of circadian blood pressure rhythm (sympathetic control) but preserved heart rate rhythm (parasympathetic regulation) only in patients with complete tetraplegia. Pathological ABPM recordings were seen in 70% of patients with symptoms of autonomic dysreflexia. CONCLUSIONS: The urodynamic examination was more sensitive in indicating signs of autonomic dysreflexia in patients with spinal cord injury, whereas SSR allowed the assessment of the degree of disconnection of the sympathetic spinal centres from supraspinal control. Using ABPM recordings the occurrence of episodes of autonomic dysreflexia over 24 hours and the effectiveness of therapeutical treatment can be assessed.