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A clear understanding of the pathophysiology and neurophysiologic effect of neuromodulation is lacking. Apparently there is a balance of efferent and afferent negative and positive feedback loops that are augmented by external electrical stimulation. This effect may be dramatic even in patients who have have not benefited from virtually every other form of treatment.
Sacral neuromodulation as a treatment for urge incontinence in patients with an unstable bladder is the subject of ongoing clinical studies. Although approximately 75% of the patients treated with a permanent sacral foramen electrode implant have experienced significant improvements, it is now also clear that there is an initial failure rate of about 25%. Recent studies have pointed out the importance of improved patient selection on the basis of sex differences, urodynamic parameters and psychological factors. Also, newer forms of test stimulation and permanent electrode implantation are being explored in an effort to improve on the present results.
The problems associated with treating various forms of lower tract dysfunction by electrical stimulation are reflected in the many years of basic and clinical research in this area. However, better understanding of both neuroanatomy and neurophysiology, and development of new technologies have led to further application of electrical current to restore impaired bladder function. Contemporary knowledge of the potential for both sacral neurostimulation and neuromodulation as a therapeutic option for lower urinary tract dysfunction is reviewed.
PURPOSE: The InterStim neuromodulator device (Medtronic, Inc., Minneapolis, Minnesota) is indicated for the treatment of refractory urge incontinence, urinary frequency and urgency, and nonobstructive urinary retention. We present a modification of the 2-stage approach which is simple to perform, reduces the number of incisions from 2 to 1, decreases operative time and potentially decreases the risk of infection. MATERIALS AND METHODS: Using a single paramedian incision, a quadripolar lead is placed into the appropriate sacral foramen. The lead is connected to the extension wire and the connector is anchored into an ipsilateral subcutaneous tunnel with the aid of an externalized polypropylene suture and plastic button. The extension wire is then externalized through the contralateral buttock using a subcutaneous tunneling device. At stage 2 the entire system can be removed through the original incision or the pulse generator can be implanted through a virgin incision over the connector site. RESULTS: A total of 20 procedures have been performed with an average stage 1 implant time of 72 minutes. Median implant time of 13 pulse generators was 36 minutes. Median explant time of 6 leads was 21 minutes. There have been no infections or adverse events. CONCLUSIONS: This modification is simple, efficient, safe and involves use of tools already familiar to urologists. By reducing the number of incisions, it reduces violation of the skin barrier and consequently risk of infection. Infection is potentially reduced at stage 2 because there is undisturbed, noncontused virgin tissue at the site of generator implant.
PURPOSE: Chronic stimulation of the sacral nerves has now become one of the most accepted stimulation therapies for functional lower urinary tract symptoms refractory to conservative treatment. Despite the existence of a large amount of literature on sacral neuromodulation (SNM) showing a fairly high percent of significant improvement in clinical outcome there are few experimental studies of SNM stimulus parameters and/or neurophysiological monitoring. We evaluated the specific action of SNM on the primary sensory cortical area. Somatosensory evoked potentials (SEPs) of the pudendal and posterior tibial nerves were evaluated in patients implanted with a monolateral permanent quadripolar electrode. MATERIALS AND METHODS: A total of 24 patients underwent stage 1 monolateral sacral nerve implantation. Three SEP patterns were evaluated; namely before implantation, 1 month after stage 1 with stimulation set at 21 Hz and again with a pulse rate of 40 Hz. RESULTS: In all patients SNM produced a significant decrease in pudendal SEP latency of the first positive deflection between baseline SNM stimulation at different pulse rates at the ipsilateral and contralateral implant sites. This finding was evidence of the effect of S3 SNM on the cortical sensory area and the specificity of pudendal SEPs in measuring how SNM modulates the afferent pathway from the spinal nerve to the cortical sensory area. CONCLUSIONS: Our study confirms previous observations that SNM acts by the afferent pathway at the cortical site level and it sheds light on so-called idiopathic lower urinary tract symptoms. A modification of SEPs induced by SNM seems to be a prognostic factor of clinical outcomes. The action of SNM on the afferent pathway from the sacral area to the somatosensory cortex is specific and neurophysiological evaluation via pudendal SEPs provides evidence to this effect.
PURPOSE: We report a prospective randomized controlled study to evaluate the possible benefits of sacral neuromodulation (SNM) for the management of neurogenic bladder dysfunction in children. MATERIALS AND METHODS: We included in the study subjects between the ages of 5 and 21 years presenting with urinary incontinence due to neurogenic bladder. Before study inclusion all previous treatment was discontinued. Patients were randomly divided into the control group treated conventionally and the implant group treated with SNM. Treatment outcome was compared every 3 months for a minimum of 12 months based on clinical examination, voiding diary and urodynamic evaluation. RESULTS: A total of 26 boys and 16 girls with a mean age of 11.9 years were enrolled in this study. There were 21 patients in each group. The main underlying etiology was spina bifida. The 2 groups were comparable with regard to sex, age and urodynamic variables. Total disappearance of urinary leakage was observed in 1 patient who underwent implantation but he still required intermittent catheterization. Comparison of urodynamic variables disclosed no significant statistical difference except with regard to functional bladder capacity which was better in the control group and the leak point pressure which was better in the implant group (p <0.05). Evaluation of interindividual variations in the implant group revealed significant improvement in compliance and functional bladder capacity at 6 and 9 months but not at 12 months. Nine patients in the implant group reported improvement in intestinal transit, 5 total disappearance of urinary infection and 6 persistent sensation of a full bladder. No patient in the control group reported any improvement. Revision surgery was required in 3 cases due to lead migration, faulty connection and wound infection. CONCLUSIONS: SNM is a promising new therapeutic modality. Implant placement is minimally invasive, nondestructive and reversible. Use in children with neurogenic bladder has not been previously reported. Although some improvement was noted in patients treated with SNM, the difference with the control group was not significant. A larger multicenter study is warranted to evaluate SNM.
INTRODUCTION: Faecal incontinence affects a percentage of the population and can have a significant effect on their ability to establish and maintain sexual relations. PATIENTS AND METHODS: Sixteen consecutive patients with permanent sacral neuromodulation (SNM) for faecal incontinence completed a 'Sex Life Questionnaire' at their follow up visit to ascertain whether there was any improvement in this aspect of their life. RESULTS: Nine of the sixteen patients was sexually active. These nine patients (median age 56 (35-61) years) had a significant reduction in faecal incontinence episodes per week from a median of 12 (1-55) to 1.5 (0-8.5) (P = 0.008). All nine patients reported that their sex life had been affected by feacal incontinence prior to SNM and seven had felt benefit from implantation. The median improvement in their sex life was 40% (1-100) and the percentage improvement was inversely correlated to age (r = -0.834, P = 0.005). CONCLUSION: SNM improves the quality of sexual activity in 78% of patients. More improvement seems to be gained the younger the patients.
OBJECTIVE: Sacral neuromodulation (SNM) has been a successful treatment in urinary voiding disorders for years. A concomitant effect on bowel function was observed leading to the treatment of faecal incontinence with SNM. In this study we describe the effect of SNM on bowel frequency and (segmental) colonic transit time. PATIENTS AND METHODS: Fourteen patients with faecal incontinence who qualified for permanent SNM underwent a colon transit study before and one month after permanent implant. Patients completed a three-week bowel habits diary before and during stimulation. RESULTS: Median incontinence episodes and days per week before SNM were, 8.7 and 4.2, respectively, and both decreased significantly to 0.67 (P = 0001) and 0.5 (P = 0001) during trial screening and to 0.33 (P = 0001) and 0.33 (P = 0001) after permanent implant. The median number of bowel movements per week decreased from 14.7 (6.7-41.7) to 10.0 (3.7-22.7)(P = 0005) during trial screening and to 10.0 (6.0-24.3)(P = 0008) during permanent stimulation. Resting and squeeze pressures did not change significantly during stimulation. Segmental colonic transit time before and during stimulation for right colon, left colon and recto sigmoid were, respectively, 6 (0-25) vs 5 (0-16) hours, 2 (0-29) vs 4 (0-45) hours and 7 (28) vs 8 (0-23) hours. No significant changes were found in both segmental and total colonic transit time; 17 (1-65) vs 25 (0-67) hours. CONCLUSION: SNM in patients with fecal incontinence led to a significant decrease of bowel movements however (segmental) colonic transit time was not influenced.
UNLABELLED: OBJECTIVE ; To review the long-term results of sacral nerve stimulation in the treatment of women with Fowler's syndrome, over a 6-year period at one tertiary referral centre. PATIENTS AND METHODS: Between 1996 and 2002, 26 women with urinary retention were treated by implanting a sacral nerve stimulator. Their case records were reviewed for follow-up, complications and revision procedures, and the most recent uroflowmetry results. RESULTS: There were 20 patients (77%) still voiding spontaneously at the time of review (with two having deactivated their stimulator because of pregnancy). Fourteen patients (54%) required revision surgery, and the most common complications included loss of efficacy, implant-related discomfort and leg pain. The mean postvoid residual volume was 75 mL and mean maximum flow rate 20.8 mL/s. CONCLUSION: In young women with retention, for whom there is still no alternative to lifelong self-catheterization, sacral neuromodulation is effective for up to 5 years after implantation. However, there was a significant complication rate, in line with other reports, which may be improved by new technical developments.
OBJECTIVE: To describe patient selection for sacral neuromodulation, also known as Interstim therapy, and the results of tined-lead implantation in the medium term. PATIENTS AND METHODS: In all, 49 patients, 39 with refractory overactive bladder symptoms and 10 with urinary retention, were implanted with the tined lead under local anaesthesia. The mean (sd) test period was 12.4 (5.8) days. Patients were implanted when they had a > or = 50% improvement in voiding diary variables during the test period. The mean follow-up for implanted patients was 15.5 (7.9) months. Changes in voiding variables were compared using a t-test. RESULTS: Ten patients had a one-stage and 39 a two-stage implant; of the latter group, 31 (80%) had a positive response and eight (21%) did not. In all, 31 patients were included in the follow-up. At the last follow-up, 28 (90%) patients had a >50% improvement in diary variables and three (10%) did not. In 21 patients with urgency symptoms the mean (sd) number of voids decreased from 11.7 (8.9)/day at baseline to 7.3 (3.4)/day (P = 0.1); the voided volume increased from 160.2 (70.7) mL to 231.1 (119.5) mL (P = 0.001); and the number of leakages decreased from 9.5 (8.7) to 3.3 (2.2)/day (P = 0.17). In the 10 patients with retention, the number of catheterizations decreased from 5.44 (1.6)/day with a volume of 297.6 (76.8) mL, to 1.2 (1.7)/day and 111.6 (158.1) mL; the mean number of voids increased from 3.7 (3.8)/day with a volume of 123.3 (141.7) mL, to 4.2 (2.4)/day and 248.3 (146.0)mL. There were no significant differences in the variables in the patients with retention. Seven patients had an adverse event. There was one incomplete electrode migration that was treated conservatively. CONCLUSION: This new minimally invasive approach gives positive results in the medium term. Two-stage testing with the tined lead seems more reliable than the classic percutaneous nerve evaluation. The lead anchoring method seems sufficient for fixing the electrode in the medium term.
OBJECTIVE: To compare changes in regional cerebral blood flow (rCBF), using positron emission tomography (PET), during chronic and acute sacral neuromodulation (SN). SN is an effective long-term treatment for chronic urge incontinence due to urinary bladder hyperactivity, as sensory nerves, spinal and supraspinal structures are probably responsible for the action of SN. It is not known which brain areas are involved, and the optimum benefit of SN is not immediate, suggesting that induced plasticity of the brain is necessary. PATIENTS AND METHODS: Brain activity was measured in two groups: 12 urge incontinent patients (11 women and one man; mean age 52 years) in whom an implanted unilateral S3 nerve neurostimulator had been effective for >6 months (mean time after implantation 4.5 years); and eight urge incontinent patients (seven women and one man; mean age 49 years) in whom the neurostimulator was activated for the first time in the PET scanner. RESULTS: During SN in chronically implanted patients, there were significant decreases in rCBF in the middle part of the cingulate gyrus, the ventromedial orbitofrontal cortex, midbrain and adjacent midline thalamus, and rCBF increases in the dorsolateral prefrontal cortex. During acute SN in newly implanted patients, there were significant decreases in rCBF the medial cerebellum, and increases in the right postcentral gyrus cortex, the right insular cortex and the ventromedial orbitofrontal cortex. Group analysis between chronic and newly implanted patients showed significant differences in the associative sensory cortex, premotor cortex and the cerebellum, all three involved in learning behaviour. CONCLUSIONS: These findings suggests that chronic SN influences, presumably via the spinal cord, brain areas previously implicated in detrusor hyperactivity, awareness of bladder filling, the urge to void and the timing of micturition. Furthermore, SN affects areas involved in alertness and awareness. Acute SN modulates predominantly areas involved in sensorimotor learning, which might become less active during the course of chronic SN.
The role of pituitary adenylate cyclase-activating polypeptide (PACAP) in catecholamine secretion from dissociated adrenal chromaffin cells of the guinea-pig was investigated using amperometry, the patch clamp technique and immunochemistry. Pretreatment of adrenal chromaffin cells with 0.3-10 nM PACAP for 2 min resulted in enhancement of nicotine- and muscarine-induced secretions in either the presence of external Ca2+ ions or nominally Ca2+-free solution, with no change in basal secretion or the holding current at -60 mV in most of the cells tested. Pretreatment with PACAP augmented the muscarine-induced non-selective cation current, but did not affect the muscarine-induced outward current or nicotine-induced current. PACAP-induced enhancement of nicotine- and muscarine-induced secretions was suppressed by the simultaneous application of PACAP and the protein kinase inhibitors 100 microM HA1004 or 2 microM H89. Application of forskolin enhanced both muscarine- and nicotine-induced secretions, whereas application of a phorbol ester augmented the nicotine-induced secretion, but suppressed the muscarine-induced secretion in a reversible manner. Immunohistochemical analysis of adrenal medullae revealed that PACAP-like immunoreactivity was present in nerve fibres surrounding putative chromaffin cells. PAC1R-like immunoreactivity was distributed diffusely in the plasma membrane, whereas nicotinic ACh receptor-like immunoreactivity was concentrated at the plasma membrane near the nucleus, where the synapses were mainly localized. These observations suggest that PACAP in the guinea-pig adrenal medulla functions as a neuromodulator to facilitate ACh-induced secretion through a cAMP-protein kinase A-dependent pathway.
The presence of the so-called trace amines 2-phenylethylamine, m-tyramine, p-tyramine, m-octopamine, p-octopamine and tryptamine in the mammalian central nervous system has been known for several decades. Despite much initial interest, these amines have largely been thought of as little more than metabolic by-products. The recent description of a family of mammalian trace amine receptors has, however, seen a resurgence of interest in the physiological role of this class of compounds. Although the trace amines are well documented to cause amphetamine-like effects, such responses only occur at concentrations multiple orders of magnitude above normal physiological levels. As such, it seems unlikely that these responses reflect the true physiological role of the trace amines. In this article previous studies showing responses to physiologically relevant concentrations of trace amines are reviewed, along with those showing a reciprocal relationship between trace amine levels and fluctuations in basal monoaminergic tone. On the basis of these studies it is hypothesized that the trace amines function as endogenous neuromodulators of classical monoamine neurotransmitters. These effects are seen as an altered neuronal sensitivity to monoamine neurotransmitters, with no change in neuronal excitability in the absence of neurotransmitter.
Age-associated deficits in learning and memory are closely correlated with impairments of synaptic plasticity. Analysis of N-methyl-D-aspartate receptor (NMDAr)-dependent long-term potentiation (LTP) in CA1 hippocampal slices indicates that the glial-derived neuromodulator D-serine is required for the induction of synaptic plasticity. During aging, the content of D-serine and the expression of its synthesizing enzyme serine racemase are significantly decreased in the hippocampus. Impaired LTP and NMDAr-mediated synaptic potentials in old rats are rescued by exogenous D-serine. These results highlight the critical role of glial cells and presumably astrocytes, through the availability of D-serine, in the deficits of synaptic mechanisms of learning and memory that occur in the course of aging.
1. We examined the neuromodulatory effects of neuropeptide Y (NPY) on purinergic and adrenergic co-transmission in the guinea-pig vas deferens. 2. In superfused vas deferens preparations, NPY (0.3 microM) inhibited the stimulus-evoked overflow of both ATP and [3H]-noradrenaline ([3H]-NA) at 2 Hz, but only the stimulus-evoked release of [3H]-NA at 20 Hz. 3. Postjunctionally, NPY greatly enhanced responses to alpha,beta-methylene ATP and to a lesser extent to exogenous NA. 4. Preparations stimulated in organ baths showed frequency-dependent contractions to field stimulation. NPY abolished responses to field stimulation at low frequency and a small number of pulses. At high frequency (20 Hz), NPY abolished responses elicited by 10 pulses, inhibited responses by 50% at 20 pulses and had little effect on preparations stimulated for 240 pulses. 5. Our study suggests that NPY neuromodulates co-transmission in the vas deferens by inhibiting the release of ATP and NA and that these effects predominate over the postjunctional enhancement by NPY. These results also show that the physiological effect of NPY will be determined both by the frequency at which the nerves are discharging and the duration of their firing.
Low back pain (LBP) is a major physical and socioeconomic entity. A significant percentage of LBP is attributable to internal disc disruption. The management of internal disc disruption has traditionally been limited to either conservative treatment or spinal fusion. Intradiscal electrothermal coagulation (IDET) and percutaneous neuromodulation therapy (PNT) are now being performed as an alternative to these therapies. Scientific data regarding the pathophysiology, biologic effects, and clinical results are relatively scarce. Early biomechanical and histologic investigations into the effects of IDET are conflicting. However, in early prospective human trials, IDET seems to provide some benefit with little risk. PNT represents a new less invasive technique for the treatment of discogenic pain, but limited research is available to determine long-term clinical efficacy. IDET and PNT are potentially beneficial treatments for internal disc disruption in carefully selected patients as an alternative to spinal fusion. More basic science and clinical research with long-term follow-up evaluation is necessary.
In this article we review our research on the development and intrinsic neuromodulation of a spinal network controlling locomotion in a simple vertebrate. Swimming in hatchling Xenopus embryos is generated by a restricted network of well-characterized spinal neurons. This network produces a stereotyped motor pattern which, like real swimming, involves rhythmic activity that alternates across the body and progresses rostrocaudally with a brief delay between muscle segments. The stereotypy results from motoneurons discharging a single impulse in each cycle; because all motoneurons appear to behave similarly there is little scope for altering the output to the myotomes from one cycle to the next. Just one day later, however, Xenopus larvae generate a more complex and flexible motor pattern in which motoneurons can discharge a variable number of impulses which contribute to ventral root bursts in each cycle. This maturation of swimming is due, in part, to the influence of serotonin released from brain-stem raphespinal interneurons whose axonal projections innervate the cord early in larval life. Larval swimming is differentially modulated by both serotonin and by noradrenaline: serotonin leads to relatively fast, intense swimming whereas noradrenaline favors slower, weaker activity. Thus, these two biogenic amines select opposite extremes from the spectrum of possible output patterns that the swimming network can produce. Our studies on the cellular and synaptic effects of the amines indicate that they can control the strength of reciprocal glycinergic inhibition in the spinal cord. Serotonin and noradrenaline act presynaptically on the terminals of glycinergic commissural interneurons to weaken and strengthen, respectively, crossed glycinergic inhibition during swimming. As a result, serotonin reduces and noradrenaline increases interburst intervals. The membrane properties of spinal neurons are also affected by the amines. In particular, serotonin can induce intrinsic oscillatory membrane properties in the presence of NMDA. These depolarizations are slow compared to the cycle periods during swimming and so may contribute to enhancement of swimming over several consecutive cycles of activity.
The gaseous neuromodulator carbon monoxide has been shown to reduce the stimulated release of stress neuropeptides, such as vasopressin and oxytocin, from the rat hypothalamus in vitro, while evidence concerning corticotropin-releasing hormone is controversial. In vivo studies have been conducted in the rat, inhibiting heme oxygenase activity--and hence carbon monoxide biosynthesis--in the central nervous system by means of specific heme oxygenase blockers; these studies showed that basal heme oxygenase activity tends to oppose exaggerated increases in vasopressin secretion following immune-inflammatory challenges, whereas it favors the normal rise in circulating ACTH which follows footshock. Another gas normally produced in mammalian brains under basal conditions, hydrogen sulfide, also appears to play a role in the control of the hypothalamo-pituitary-adrenal axis. Indeed, increases in hydrogen sulfide levels within the hypothalamus, either obtained with hydrogen sulfide-enriched media or by the addition of the hydrogen sulfide precursor S-adenosyl-methionine, are associated with the inhibition of the stimulated release of corticotropin-releasing hormone from rat hypothalamic explants. Parellel in vivo experiments in the rat under resting conditions and after stress-induced adrenocortical activation show that S-adenosyl-methionine significantly reduces the rise in serum corticosterone levels caused by 1-h exposure to cold. These results demonstrate the pathophysiological importance of both carbon monoxide and hydrogen sulfide in the regulation of neuroendocrine function.