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PubMed2000

Neuromodulation reduces urinary frequency in rats with hydrochloric acid-induced cystitis.

OBJECTIVE: To evaluate the effect of sacral neuromodulation on interstitial cystitis (IC) and determine the underlying mechanism of neuromodulation in the treatment of IC. Materials and methods Twenty Sprague-Dawley rats (body weight 220-250 g) were randomly divided into four equal groups; normal controls, a sham treatment (IC induced by 0.4 mol/L HCl, + saline), a second sham treatment (HCl-induced IC + acetic acid) and a stimulated group (HCl-induced IC + acetic acid, with electrical stimulation). In the last group bilateral electrodes were implanted into the S1 dorsal foramina and electrical stimulation applied for 8 h/day for 3 weeks. Acetic acid was instilled into the bladder to induce c-fos expression. After 3 weeks the rats were perfused with 4% paraformaldehyde, spinal segments dissected out and an immunocytochemical method used to stain the segments for fos protein encoded byc-fos. RESULTS: The mean (SEM) micturition frequency (voids/17 h) in the sham groups increased from 10.8 (2.7) to 23.4 (3.4) 3 weeks after the intravesical instillation of HCl. The micturition frequency in the stimulated group, at 16.2 (2.7), was significantly less than in the sham group (P = 0.04) after electrical stimulation for 3 weeks. There was no significant difference in the mean (SEM) number of fos-positive neurones in the L6 spinal cord segment between the stimulated and the sham + acetic acid group, at 43.6 (9.4) and 35.8 (7.8) cells/section, respectively (P = 0.32). CONCLUSIONS: In rats with HCl-induced cystitis, electrical stimulation reduced the micturition frequency, but not by inhibiting afferent c-fibre activity.

Animals↗

PubMed2002

Long-term efficacy and safety results of the two-stage implantation technique in sacral neuromodulation.

OBJECTIVE: To assess the long-term efficacy and safety of two-stage sacral neuromodulation with an implantable pulse generator (IPG) in patients treated for urinary urge incontinence (UI) and/or urinary retention (UR). PATIENTS AND METHODS: The two-stage technique is used if patients have a good response during the acute phase of the percutaneous nerve evaluation (PNE) test, but have a poor response during the following 4-7 days (subchronic phase). In the first stage only the permanent electrode was implanted and connected to a temporary external stimulator, allowing patients to be assessed for longer. If the main symptoms improved by more than half the patient proceeded to the second stage, the insertion of the IPG. We reviewed all patients who underwent two-stage implantation; all had signed an informed consent and were asked to complete voiding diaries and a questionnaire to assess the subjective effects of the therapy. Safety was assessed from relevant medical events, management, and relative to the thera-py and resolution. Residual urine was assessed by self-catheterization. The long-term voiding diary results were compared with baseline estimates and analysed statistically using the two-sided Student's t-test. RESULTS: Between 1991 and 1998, 15 patients (13 women and two men, mean age 53 years, range 44-66) underwent the two-stage technique; the mean (median, range) follow-up was 4.9 (5.2, 2.5-7.5) years. Seven patients had UI and seven had UR, with one having both. The mean (range) number of PNEs undertaken in each patient was 2.1 (1-4) and these all failed in the subchronic phase. All patients underwent a first- and second-stage implant after a mean (range) screening period of 12.2 (2-29) days. One patient was explanted after implantation of only the first stage, and two others explanted in a later phase because the IPG was ineffective during the follow-up. The voiding diary results of the remaining 12 patients showed improvement in all the main variables, and in the subjective assessment 11 reported an improvement and were satisfied with the therapy. There were 17 adverse events, 14 of which were resolved and seven of which required surgical intervention. CONCLUSION: The long-term results of the two-stage implantation show clinically and statistically significant improvements, probably because the implantation of the lead (first stage) more closely resembles the final therapy. If a temporary PNE test is not optimal (lead migration, longer testing needed), the two-stage technique can offer a good and safe alternative of comparable efficacy in the long-term. If the two-stage technique had not been available to these 12 patients they would not have been offered neuromodulation.

Adult↗

PubMed2003

Improved sacral neuromodulation in the treatment of the hyperactive detrusor: signal modification in an animal model.

OBJECTIVE: To investigate different stimulation signals for the peripheral nerve evaluation test (PNE, carried out before implanting a sacral neuromodulator for functional voiding dysfunction) in an animal model and to determine their efficacy, as up to 80% of patients do not respond to the PNE test. MATERIALS AND METHODS: PNE foramen electrodes were placed in the S3 of 12 anaesthetized Göttingen minipigs. First, detrusor instabilities were induced by the intravesical instillation of formalin. A 10-min stimulation phase with both a quasi-trapezoidal (QT) signal and a rectangular signal followed. An interval of 30 min elapsed between the series of stimulations. The attained bladder pressure values were registered on a urodynamic unit and evaluated as contractions and amplitudes per minute. Six minipigs were treated in the same way but were not stimulated and served as a control group. RESULTS: After formalin instillation, the mean (sd) number of involuntary detrusor contractions was 3.5 (0.8)/min and the sum of amplitudes 7.2 (1.1) cmH2O/min. Subsequent NaCl instillation and QT-stimulation reduced the contractions to 0.3 (0.3)/min and the sum of amplitudes to 0.8 (0.4) cmH2O/min. Stimulation with a rectangular signal, as used in the PNE test, followed after an interval of 10 min, giving 1.1 (0.1) contractions/min and a sum of amplitudes of 5.1 (2.4) cmH2O/min. Within the control group there was no significant reduction. CONCLUSIONS: These results show that QT-stimulation suppresses uncontrollable detrusor contractions in the minipig more effectively than the conventional rectangular stimulation presently applied in sacral neuromodulation.

Animals↗

PubMed2005

[Pudendal nerve stimulation therapy of the overactive bladder -- an alternative to sacral neuromodulation?].

PURPOSE: Sacral neuromodulation is known to be an alternative therapeutic option for patients with anticholinergic resistant overactive bladder (OAB). For the same indication, a microstimulation system called BION is available since last year. The BION-stimulator, which only measures 2.8 x 0.3 cm, is designed for pudendal nerve stimulation. Its implantation technique as well as the first clinical results are presented and discussed. MATERIALS AND METHODS: During an outpatient percutaneous screening test (PST), a pudendal nerve stimulation is performed with a needle electrode in local anesthesia. A 50 % increase in the urodynamic parameters (bladder capacity, first desire to void, compliance, etc.) is an indication for a chronic implantation of the BION stimulator, which also can be placed in local anesthesia. RESULTS: Two patients have been treated with a BION-stimulator in our clinic so far. Patient I suffered from an OAB with frequent urinary incontinence and patient II had a sensory OAB with high voiding frequency. After the BION(R)-implantation, patient I showed a reduction in incontinence episodes by 31.5 % a day and patient II had lowered voiding frequencies from 12.6 to 7 a day. The postoperative urodynamic investigations confirmed these clinical results. CONCLUSIONS: The BION-system and chronic pudendal nerve stimulation seem to be alternatives to sacral neuromodulation, however, patient selection is difficult as subchronic stimulation for a longer period of time is not possible so far.

Aged↗

PubMed2002

Sacral neuromodulation in an older, urge-incontinent population.

OBJECTIVE: The success of sacral neuromodulation in the treatment of urge incontinence has been reported in young populations. Herein we report the success in an older, urge-incontinent population. STUDY DESIGN: A cohort of 25 patients older than 55 years who had failed conventional therapy for the treatment of urge incontinence underwent percutaneous S3 sacral nerve test stimulation. Patients were considered candidates for permanent implantation if they were cured or had a greater than 50% improvement in incontinent episodes. Responders were implanted and completed a questionnaire, bladder diary, and disease-specific quality-of-life questionnaire. RESULTS: Twelve of the 25 patients (48%) responded to the test stimulation. The average follow-up after permanent implantation was 7.8 months. All patients obtained a >50% reduction in their incontinent episodes; 2 patients achieved total dryness. CONCLUSION: Our small cohort suggests that older urge-incontinent patients have improvement with sacral neuromodulation but cure rates may be lower than with a younger population.

Aged↗

PubMed2002

Sacral neuromodulation in Norway: clinical experience of the first three years.

We present our first three years' experience of sacral neromodulation as first line therapy in patients with a non-neurogenic refractory urge incontinence. In 53 patients, 45 women and 8 men with a mean age of 54 years (range 17-76 years), tested by subacute percutan nerve evaluation, 19 patients were declared as responders according to our programme. Fourteen patients, twelve women and two men with a mean age of 47 years (range 33-73 years), agreed to implantation of a neuroprosthesis (Medtronic Interstim Model 3031), which was placed in a subcutaneous buttock pocket in 12 patients. In the first two patients, the device was implanted subcutaneously corresponding to the lower quadrants of the abdominal wall. In two patients, the lead was repositioned from S:4 to S:3 six to twelve months after the primary implantation. In one woman with sensory urgency, the neuroprosthesis was removed six months after it was implanted because of failure. The patients were followed every six months using voiding diary, uroflowmetry, residual urine and cystometry. Eight patients reported total continence, and five declared >50% improvement. One woman has chronic bacteriuria and intermittently symptomatic urinary tract infection, which reduce the response to the chronic sacral nerve stimulation. Because of residual urine, four women are following an individual self-catheterisation programme. In conclusion, we have documented that sacral neuromodulation is an effective and safe procedure in patients with refractory urge incontinence depending on detrusor overactivity. We confirm the clinical results reported by other centres with long experience of sacral neuromodulation.

Electric Stimulation Therapy↗

PubMed2000

A neuromodulation strategy for rational therapy of complex brain injury states.

We review initial efforts at neuromodulation in the vegetative state and organize several aspects of recent studies of the underlying neurobiology of catastrophic brain injuries. An innovative strategy for patient and target selection for neuromodulation of impaired cognitive function is outlined. Scientific and ethical issues that will attend future efforts to appropriately risk-stratify patients and initiate interventions with therapeutic intent are considered.

Brain↗

PubMed2004

Sacral nerve neuromodulation and fecal incontinence: Indications, technique, and results.

This article reviews the use of sacral neuromodulation (SNM) for fecal incontinence. Six case series and one crossover study in which sacral neuromodulation had been used for people with fecal incontinence were selected for assessment. Primary outcomes included the number of fecal incontinent episodes per week, ability to defer defecation and quality of life. Following implantation, 41-75% of patients achieved complete fecal continence and 75-94% experienced improvement in incontinent episodes. The ability of patients to be able to defer defecation and fecal incontinence specific quality of life scores had also improved. There were 19 adverse events amongst 149 patients. The small crossover study reported increased episodes of fecal incontinence when the implantable pulse generator (IPG) was switched off. The evidence suggests that SNM achieves a significant improvement in patients with fecal incontinece resistant to conservative treatment. Follow-up indicates that improvements are maintained over the medium term.

Journal Article↗

PubMed1996

Neuromodulation of transduction and signal processing in the end organs of taste.

Chemical synapses transmit gustatory signals from taste receptor cells to sensory afferent axons. Chemical (and electrical) synapses also provide a lateral pathway for cells within the taste bud to communicate. Lateral synaptic pathways may represent some form of signal processing in the peripheral end organs of taste. Efferent synaptic input may also regulate sensory transduction in taste buds. To date, the synaptic neurotransmitter(s) or neuromodulator(s) released at chemical synapses in taste buds have not been identified unambiguously. This paper summarizes the attempts that have been made over the past 40 years to identify the neuroactive substances acting at taste bud synapses. We review the four traditional criteria for identifying chemical transmitters elsewhere in the nervous system-localization, uptake/degradation, release and physiological actions- and apply these criteria to neuroactive substances in taste buds. The most complete evidence to date implicates serotonin as a neuromodulator of taste transduction in the end organs. However, studies also suggest that adrenergic, cholinergic and peptidergic neurotransmission may be involved in taste buds.

Animals↗

PubMed2000

The involvement of adenosine neuromodulation in pentobarbital-induced field excitatory postsynaptic potentials depression in rat hippocampal slices.

We investigated the contribution of adenosine neuromodulation to mechanisms of pentobarbital-induced depression of excitatory synaptic transmission in vitro. Transverse hippocampal slices were prepared from brains removed from isoflurane-anesthetized male Wistar rats. Field excitatory postsynaptic potentials (fEPSPs), elicited by orthodromic electrical stimulation of Schaffer collateral at 0.05 Hz, were recorded from the CA1 region in oxygenated artificial cerebrospinal fluid. Amplitude of fEPSP was analyzed for assessing drug effects. Pentobarbital (100 microM) transiently depressed fEPSPs (P<0.01); i.e., fEPSP was initially depressed to approximately 60% of control and then recovered to approximately 80% of control. The fEPSP depression was partially suppressed by pretreatment with 50 microM aminophylline, a nonselective adenosine receptor antagonist, and 0.2 microM 3, 7-Dimethyl-1-propagylxanthine, an adenosine A(1) receptor antagonist (P<0.01 each). However, the fEPSP depression was not affected by pretreatment with 10 microM 8-cyclopentyl-1, 3-dipropylxanthine, an A(2) receptor antagonist, or 10 microM bicuculline, a gamma-aminobutyric acid (GABA) A receptor antagonist. The results indicate that adenosine neuromodulation through A(1) receptors and other undefined mechanisms, which are independent from GABAergic mechanisms, are involved in pentobarbital-induced depression of excitatory synaptic transmission.

Adenosine↗

PubMed2002

New trends in neuromodulation for the management of neuropathic pain.

Since its first application in 1967, the methodology and technology of spinal cord stimulation for the management of chronic, intractable pain have evolved continuously. Despite these developments and improved knowledge of the effects of spinal anatomy and epidural contact configuration on paresthesia coverage, the clinical results of spinal cord stimulation-particularly the long-term effects-are still unsatisfactory in many patients. This dissatisfaction has come primarily from the failure of single-electrode configurations to provide consistent paresthesia coverage of the entire painful area. Therefore, new approaches were developed during the late 1990s that attempted to selectively cover one or more dermatomes with paresthesia as well as to provide sequential stimulation of different anatomic sites. These approaches have been applied both intraspinally and extraspinally by stimulating either the spinal nerves or the dorsal columns. To target parts of the latter, different methods have been developed and tested using either two-dimensional contact configurations or electronic field steering. These developments hold promise for improving long-term outcomes as well as increasing the number of pain conditions that can be treated with neuromodulation therapy. In this review, the history, theoretical basis, and evolution of these methodologies, as well as the ways in which they represent new trends in neuromodulation, are discussed.

Electric Stimulation Therapy↗

PubMed2003

Sacral neuromodulation for the symptomatic treatment of refractory interstitial cystitis: a prospective study.

PURPOSE: The efficacy of sacral neuromodulation for the treatment of symptoms in patients with refractory interstitial cystitis was evaluated. MATERIALS AND METHODS: A total of 25 patients with a mean age of 47 years and refractory interstitial cystitis were prospectively evaluated with a trial of sacral nerve stimulation. Patients who demonstrated 50% improvement in frequency, nocturia, voided volume and average pain qualified for permanent sacral nerve stimulator implantation. Treatment success was measured by voiding diary, report of average pain, and response to the Interstitial Cystitis Symptom Index and Interstitial Cystitis Problem Index. RESULTS: Of the 25 patients 17 qualified for permanent sacral nerve stimulator implantation. At an average of 14 months followup mean daytime frequency and nocturia improved from 17.1 to 8.7 and 4.5 to 1.1, respectively (p <0.01). Mean voided volume increased from 111 to 264 ml. (p <0.01). Report of average pain decreased from 5.8 to 1.6 points on a scale of 0 to 10 (p <0.01). Interstitial Cystitis Symptom and Problem Index scores decreased from 16.5 to 6.8 and 14.5 to 5.4, respectively (p <0.01). Of the 17 patients 16 (94%) with a permanent stimulator demonstrated sustained improvement in all parameters at the last postoperative visit. CONCLUSIONS: Results of this prospective clinical study demonstrate that sacral neuromodulation is a safe and effective treatment for the dysfunctional voiding and pelvic pain in patients with interstitial cystitis who are refractory to other forms of treatment.

Adult↗

PubMed2004

Sacral neuromodulation decreases narcotic requirements in refractory interstitial cystitis.

OBJECTIVE: To assess the efficacy of long-term sacral neuromodulation (InterStim(R), Medtronic Inc., Minneapolis, MN) in treating chronic pelvic pain associated with interstitial cystitis (IC, a symptom complex of urinary urgency, frequency and pelvic pain, often necessitating narcotics) refractory to standard therapy. PATIENTS AND METHODS: Twenty-one patients (17 female, four male, mean age 45.5 years, range 17-68) with refractory IC with chronic pelvic pain were reviewed retrospectively. In these patients a mean of six previous treatments for IC had failed. All patients had had cystoscopy and hydrodistension to confirm their diagnoses. All had a permanent InterStim device implanted by one surgeon (K.M.P.) between 2000 and 2002, after responding to a temporary test. Data were collected from chart reviews and patient questionnaires. Intramuscular morphine dose equivalents (MDEs) were calculated before and after implantation. RESULTS: All 21 patients responded to the questionnaire; the mean (range) follow-up after implantation was 15.4 (7.4-23.1) months. Eighteen patients used chronic narcotics before the InterStim and 20 reported moderate or marked improvement in pain afterward. The mean MDE decreased from 81.6 to 52.0 mg/day (36%) after implantation (P = 0.015). Four of 18 patients stopped all narcotics after InterStim implantation. CONCLUSIONS: Sacral neuromodulation decreases narcotic requirements and subjective pelvic pain in patients with refractory IC. Further decreases in MDE are anticipated as dose reductions continue in patients who improved.

Adolescent↗

PubMed1999

Neurotransmitters and neuromodulators controlling the hypoxic respiratory response in anaesthetized cats.

1. The contributions of neurotransmitters and neuromodulators to the responses of the respiratory network to acute hypoxia were analysed in anaesthetized cats. 2. Samples of extracellular fluid were collected at 1-1.5 min time intervals by microdialysis in the medullary region of ventral respiratory group neurones and analysed for their content of glutamate, gamma-aminobutyric acid (GABA), serotonin and adenosine by high performance liquid chromatography. Phrenic nerve activity was correlated with these measurements. 3. Levels of glutamate and GABA increased transiently during early periods of hypoxia, coinciding with augmented phrenic nerve activity and then fell below control during central apnoea. Serotonin and adenosine increased slowly and steadily with onset of hypoxic depression of phrenic nerve activity. 4. The possibility that serotonin contributes to hypoxic respiratory depression was tested by microinjecting the 5-HT-1A receptor agonist 8-OH-DPAT into the medullary region that is important for rhythmogenesis. Hypoxic activation of respiratory neurones and phrenic nerve activity were suppressed. Microinjections of NAN-190, a 5-HT-1A receptor blocker, enhanced hypoxic augmentation resulting in apneustic prolongation of inspiratory bursts. 5. The results reveal a temporal sequence in the release of neurotransmitters and neuromodulators and suggest a specific role for each of them in the sequential development of hypoxic respiratory disturbances.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1998

Neuromodulation intrinsic to the central pattern generator for escape swimming in Tritonia.

Extrinsic neuromodulatory inputs to central pattern generators (CPGs) can alter the properties and synaptic interactions of neurons in those circuits and thereby modify the output of the CPG. Recent work in a number of systems has now demonstrated that neurons intrinsic to CPG can also evoke neuromodulatory actions on other members of the CPG. Such "intrinsic neuromodulation" plays a role in controlling the CPG underlying the escape swim response of the nudibrach mollusc, Tritonia diomedea. The dorsal swim interneurons (DSIs) are a bilaterally represented set of three serotonergic neurons that participate in the generation of the rhythmic swim motor program. Serotonin released from these CPG neurons functions both as a fast neurotransmitter and as a slower neuromodulator. In its modulatory role, serotonin enhances the release of neurotransmitter from another CPG neuron, C2, and also increases C2 excitability by decreasing spike frequency adaptation. These neuromodulatory actions intrinsic to the CPG may be important for the initial self-configuration of the system into a function CPG and for experience-dependent changes in the output such as behavioral sensitization and habituation.

Animals↗

PubMed2001

High-pass filtering of corticothalamic activity by neuromodulators released in the thalamus during arousal: in vitro and in vivo.

The thalamus is the principal relay station of sensory information to the neocortex. In return, the neocortex sends a massive feedback projection back to the thalamus. The thalamus also receives neuromodulatory inputs from the brain stem reticular formation, which is vigorously activated during arousal. We investigated the effects of two neuromodulators, acetylcholine and norepinephrine, on corticothalamic responses in vitro and in vivo. Results from rodent slices in vitro showed that acetylcholine and norepinephrine depress the efficacy of corticothalamic synapses while enhancing their frequency-dependent facilitation. This produces a stronger depression of low-frequency responses than of high-frequency responses. The effects of acetylcholine and norepinephrine were mimicked by muscarinic and alpha(2)-adrenergic receptor agonists and blocked by muscarinic and alpha-adrenergic antagonists, respectively. Stimulation of the brain stem reticular formation in vivo also strongly depressed corticothalamic responses. The suppression was very strong for low-frequency responses, which do not produce synaptic facilitation, but absent for high-frequency corticothalamic responses. As in vitro, application of muscarinic and alpha-adrenergic antagonists into the thalamus in vivo abolished the suppression of corticothalamic responses induced by stimulating the reticular formation. In conclusion, cholinergic and noradrenergic activation during arousal high-pass filters corticothalamic activity. Thus, during arousal only high-frequency inputs from the neocortex are allowed to reach the thalamus. Neuromodulators acting on corticothalamic synapses gate the flow of cortical activity to the thalamus as dictated by behavioral state.

Acetylcholine↗

PubMed2000

Sacral neuromodulation for women with Fowler's syndrome.

Neuromodulation of the sacral nerves has been found to be an effective therapy for a variety of lower urinary tract dysfunctions. The reported success rate for the period of trial stimulation (peripheral nerve evaluation test) prior to permanent implantation of a sacral nerve stimulator is variable, but generally reported to be in the region of 30-50%. We present here the results of the peripheral nerve evaluation test in 38 patients with urinary retention. 34 of the 38 had been found to have an abnormality of their striated urethral sphincter on electromyography using a concentric needle electrode, i.e., they had the disorder which was described by Fowler and coworkers in 1988. The overall success rate in this group was 68%. We believe that our relatively high success rate is due to sacral neuromodulation working via a mechanism which involves the urethral sphincter, an abnormality which had been demonstrated in 89% of these patients. Twelve of the patients subsequently underwent permanent implantation of a sacral nerve stimulator, and all of them have experienced a return of voiding. However, in 2 patients, there is a persisting need for self-catheterization. There is, however, a high reoperation rate.

Adolescent↗

PubMed1993

Neuromodulation of sacral nerves for incontinence and voiding dysfunctions. Clinical results and complications.

Neuromodulation of sacral nerves is a new form of treatment for patients with refractory voiding dysfunctions such as incontinence, retention and chronic pelvic pain. Electrical stimulation of S3 activates the pelvic floor and modulates innervation of the bladder, sphincter and pelvic floor, restoring the balance and coordination in sacral reflexes. 19 of 23 patients with an implanted neuroprosthesis for neuromodulation have a more than 50% improvement in their main symptoms after a median follow-up of 12 months. In urge-incontinent patients the number of leakings decreased from 7.4 to 1.5/day, and the functional capacity increased from 135 to 227 ml.

Abdominal Pain↗