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PubMed2002

Interleukin-6 (IL-6): a possible neuromodulator induced by neuronal activity.

IL-6 and its receptor(s) are found in the CNS in health and disease. Cellular sources are glial cells and neurons. Glial production of IL-6 has intensively been studied, but comparatively little is known about the induction of IL-6 in neurons. Emerging evidence suggests that IL-6 possesses neurotrophic properties. Recent data show that neuronal IL-6 expression is induced by excitatory amino acids or membrane depolarization. This implicates that IL-6 is produced not only under pathological conditions but may play a critical role as a physiological neuromodulator that is induced by neuronal activity and regulates brain functions. In the following article, the authors review the current data on IL-6 expression in neurons, with special reference to the induction of IL-6 by neuronal activity. They discuss its direct and indirect effects as a neuromodulator and speculate about the possible function of IL-6 as a physiological regulatory molecule and as a neuroprotective agent in brain pathology.

Animals↗

PubMed2006

Sacral nerve neuromodulation for the treatment of lower bowel motility disorders.

INTRODUCTION: Incontinence and constipation are common and cause a high degree of physical, social and psychological impairment. Maximal conservative therapy may improve some patients but many remain symptomatic. Surgical options are often unsatisfactory, with variable result and further options are limited. Sacral nerve stimulation uses electrical stimulation applied to the sacral nerves, eliciting a physiological effect on the lower bowel, anal sphincter and pelvic floor, resulting in clinical benefit. The objective of this study was to investigate whether sacral nerve neuromodulation can improve patients with disorders of bowel motility, when current maximal treatment has failed and to investigate the underlying physiological mechanism of action. RESULTS: Incontinence: Nineteen patients, age 58 years (range, 37-71 years), with resistant incontinence for 6 years (range, 2-21 years) underwent stimulation. Continence improved in all at 24 months (range, 3-60 months), fourteen fully continent. Incontinent episodes decreased; 12 (range, 2-30) versus 0 (range, 0-4), P < 0.001. Urgency (P < 0.01) and quality of life improved (P < 0.05). Anal squeeze pressure (P = 0.001) and rectal sensation (P < 0.01) improved. Constipation: Four women, (aged 27-36 years) with resistant idiopathic constipation for 8-32 years underwent the first worldwide implants. Symptoms improved in all with temporary, and in three with permanent, stimulation at 8 months (range, 1-11 months). Bowel frequency increased: 1-5 versus 6-28 evacuations/3-weeks. Symptom scores and quality of life improved. Placebo effect: A double-blind, cross-over study was performed to examine placebo effect and efficacy. Once stimulation was removed, in a blinded manner, symptoms, physiological parameters and quality of life measures rapidly returned to baseline levels. Autonomic neuromodulation: Sixteen patients, median age 59 years (range, 38-71 years), were studied at 27 months (range, 2-62 years) using laser Doppler flowmetry. Chronic stimulation was at 2.8 V (range, 0.3-3.9 V). Median flux differed between none and chronic stimulation (P = 0.001). Step-wise increments caused an immediate, dose-dependent rise in flux (P < 0.0001) up to 1.0 V. CONCLUSIONS: This research provides strong evidence that sacral nerve stimulation can improve patients with resistant incontinence and shows proof-of-concept for the treatment of constipation. The effect is unlikely to be due to placebo and the mechanism is rapidly reversible and involves a dose-dependent effect on the autonomic nerves.

Adult↗

PubMedDate not supplied

Spinal-Cord plasticity: independent and interactive effects of neuromodulator and activity-dependent plasticity.

Plasticity is one of the most extensively studied aspects in neuroscience. Interest in it has primarily been related to its proposed role in learning and memory and its relevance to adaptive changes following injury. Plasticity can be evoked by changes in molecular, cellular, and synaptic properties, either as a result of activity-dependent effects, or by relatively slow-acting neuromodulatory transmitters. In addition, it is increasingly recognized that the plasticity evoked by these individual effects can be altered by previous inputs and is thus itself plastic. Here, I will review studies in the lamprey spinal cord that have examined individual and interactive activity-dependent and neuromodulator-mediated plasticity. The results show that activity-dependent and neuromodulator-mediated plasticity evoke neuron-and synapse-specific effects at different levels in the spinal cord, and that interactions within and between these effects can evoke dynamic changes in cellular, synaptic, and network plasticity.

Action Potentials↗

PubMed1998

Different putative neuromodulators are present in the nerves which distribute to the teleost skeletal muscle.

The presence of putative neuromodulators in the nerve fibres was investigated in white skeletal muscle of two teleost fish not taxonomically correlated and showing different patterns of innervation (multiple versus focal innervation). Cryostat sections of epaxial, hypaxial and adductor mandibulae (AM) muscles of Sparus aurata and Anguilla anguilla were stained histochemically for reduced nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase. Other sections were used for indirect immunohistochemistry (streptavidin-biotin and rhodamine immunofluorescence methods), employing antibodies specific for putative excitatory or inhibitory peptides, including CGRP, substance P, met-enkephalin, bombesin, and VIP. In addition, ultrastructural observations were performed in order to describe the morphology of the motor endplates. A strong immunoreactivity for CGRP and substance P was found in many nerve terminals. Met-enkephalin, bombesin and VIP immunoreactivities were less frequently observed. No immunoreactivity was observed to CCK, NPY or 5-HT. NADPH-diaphorase was identified in nerve fibres of the AM complex only of A. anguilla. Electron microscopy observations evidenced more than one type of synaptic vesicle in motor endplates. Some differences in putative neuromodulator distributions were observed in the two species and muscle complexes, which may be related to the different taxonomical position as well as the different pattern of innervation of white muscle fibres.

Anguilla↗

PubMed2006

High sensitivity to neuromodulator-activated signaling pathways at physiological [K+] of confocally imaged respiratory center neurons in on-line-calibrated newborn rat brainstem slices.

The pre-Bötzinger complex (PBC) inspiratory center remains active in a transverse brainstem slice. Such slices are studied at high (8-10 mM) superfusate [K+], which could attenuate the sensitivity of the PBC to neuromodulators such as opiates. Findings may also be confounded because slice boundaries, drug injection sites, or location of rhythmogenic interneurons are rarely verified histologically. Thus, we first generated PBC slices with defined boundaries using novel "on-line histology" based on our finding that rostrocaudal extensions of brainstem respiratory marker nuclei are constant in newborn rats between postnatal days 0-4. At physiological superfusate [K+] (3 mM), 500- and 600-microm-thick slices with the PBC in the center and the caudal boundary 0.70 and 0.76 mm caudal to the facial motonucleus generated rhythm for >2 and approximately 4 h, respectively. Rhythm was abolished by low nanomolar concentrations of the mu-opiate receptor agonist DAMGO ([D-Ala2, N-Me-Phe4, Gly5-ol]enkephalin). After spontaneous arrest of bursting, rhythm was reactivated at clinically relevant or physiological concentrations by 3,5-dihydroxyphenylglycine, thyrotropin-releasing hormone, or rolipram, each affecting distinct second-messenger pathways. Two-photon/confocal Ca2+ imaging revealed that these agents reactivated the same PBC neurons initially active in 3 mM [K+]. The data show that "calibrated" PBC slices at physiological [K+] generate rhythm with a high sensitivity to neuromodulators for extended time periods, whereas spontaneous "in vitro apnea" is an important tool to study the interaction of signaling pathways that modulate rhythm. Our approaches and findings provide the basis for a pharmacological and structure-function analysis of the isolated respiratory center in a histologically well defined substrate at physiological [K+].

Action Potentials↗

PubMedDate not supplied

Applications of neuromodulation of the lower urinary tract in female urology.

Neuromodulation is becoming part of clinical armamentarium for treatment of a variety of lower urinary tract conditions in female urology. Its increased usage stems from need of patients who have exhausted all other therapeutic options for their complex and poorly understood lower urinary tract disorders. Currently neuromodulation may consist of the use of sacral nerve stimulation (SNS) and injectable therapies. Herein, we will discuss the background and development of SNS, its current indications, methods of patient selection and will review the results of the recent published literature on SNS. In addition, we will discuss some of the newer developments in SNS such as Bion device and the future direction in integration of SNS in female urology.

Clinical Trials as Topic↗

PubMed2000

Sacral nerve neuromodulation in the treatment of patients with refractory motor urge incontinence: long-term results of a prospective longitudinal study.

PURPOSE: Conservative treatment rarely results in a durable cure of patients with urge incontinence and bladder overactivity. Instrumental and surgical procedures often have significant side effects and less than optimal results. We developed a technique of sacral nerve neuromodulation using chronic unilateral electrical stimulation of the S3 sacral nerve to inhibit the micturition reflex to provide effective nondestructive alternative therapy for patients whose condition is refractory to conservative treatment. MATERIALS AND METHODS: Of 85 patients 45 who responded to a test with a temporary electrode underwent implantation of a permanent S3 sacral nerve electrode coupled to a pulse generator. Treatment results were evaluated by urodynamic studies and voiding/incontinence diaries documenting pad use, incontinence episodes, voiding frequency and voided volume. Partial success and cure were defined as 50% to 90% and more than 90% improvement, respectively, in pad use and/or incontinence episodes. RESULTS: Of 45 patients 18 (40%) were cured at an average followup of 47.1 months and 9 (20%) achieved partial success. Median number of pads used and median number of incontinence episodes daily had decreased from 5.4 to 1.2 (p = 0.0001) and 7.1 to 1.3 (p = 0.0001), respectively, 6 months after implantation. Subsequently these results remained almost constant for 5 years. Bladder overactivity disappeared in 19 of the 44 patients (43%). The repeat intervention rate was 37.7% and there was no permanent injury or nerve damage. CONCLUSIONS: Sacral nerve neuromodulation is safe, effective and durable in patients with urge incontinence refractory to conservative treatment.

Adolescent↗

PubMed2001

Effects of continuous microchip (MC) vagal neuromodulation on gastrointestinal function in rats.

Afferent fibers from gastrointestinal tract outnumber efferents ten times in vagal nerves. Modifying the afferent input makes possible to change discharge of vagal efferents affecting gastrointestinal functions in process known as neuromodulation (NM). Lately it has been used in the treatment of pain and hyperactive neurogenic bladder in urology. MC induced NM may therefore provide a concurrent to pharmacology tool, in treatment of gastrointestinal disorders. The aim of this study was to investigate the effects of long term neuromodulation procedure with use of MC on gastric motility, secretion and weight control in conscious rats. Experiments were performed on 30 Wistar male rats (250-350 g) divided in two groups: sham operated and microsurgically implanted with MC on left vagal nerve below diaphragm. Following stimulation parameters were used: frequency of 0.5-30 Hz, amplitude of 0.55 V, impulse duration of 10 ms in monophasic fashion. In both groups food intake and body weight were measured through the period of 2 weeks after recovery period. Then gastric fistula was implanted in gastric antrum and fasted gastric motility recorded with use of PowerLab system (Australia). Gastric emptying and secretion were also tested with use of phenol red and automatic titration methods. On the daily basis glucose level with standard test and leptin after MC implantation were measured. Recording of vagal activity in fasted rats showed burst of action potentials about 5 +/- 2.5 in period of 5000 sec, each burst with spike frequency up to 35 Hz. Food (5 ml of Intralipid--intragastrically) almost doubled amount of bursts to 12 +/- 5 in period of 5000 sec with increase in frequency at spike up to 50 Hz. MC induced vagal activity showed continuous spike activity similar to fed pattern. MC induced NM decreases daily food intake by 6% (33.6 +/- 4.8 vs control 35.5 +/- 4.8 g, p < 0.01). Body weight gain in rats before MC implantation decreased by 20% within 2 weeks after recovery (34.8 +/- 9.08 vs control 23.56 +/- 4.15 g). Fasting control glucose level also decreased of 5.5% (93.15 +/- 9.3 vs control 98.5 +/- 11.2 mg%, p < 0.05). Frequency of gastric contractions did not change significantly in MC versus control but amplitude of contractions increased of about 66.7% (2.0 +/- 0.8 vs 1.17 +/- 0.52) at the dominant frequency 0.08 Hz range and about 71.5% (1.17 +/- 0.35 vs 0.68 +/- 0.47, p < 0.05) at the frequency 0.12 Hz. in FFT analysis PowerLab (chart v = 4.01). BAO decreased by 29.25% without H+ concentration changes (0.2 +/- 0.14 vs 0.14 +/- 0.12 mmol/30 min, p < 0.05) but MAO did not change in MC rats (0.37 +/- 0.25 vs 0.42 +/- 0.28 mmol/30 min, p 0.05). Gastric emptying of isotonic solution increased by 10% (90.46 +/- 5.34 vs 80.39 +/- 9.95) percent of marker passing to duodenum/5 min, p < 0.0001). Our results suggest that MC induced NM affect brain-gut axis via influencing metabolic and gastric function and decreases body weight.

Animals↗

PubMedDate not supplied

[A unified postsynaptic mechanism for the effect of various neuromodulators on modification of potentiated and depressed inputs to hippocampal cells (hypothesis)].

The unitary postsynaptic mechanism underlying the influence of diverse neuromodulators on modification of excitatory and inhibitory inputs to granule, pyramidal and inhibitory hippocampal cells is suggested. According to this mechanism, the effect of dopamine, adenosine, acetylcholine, noradrenaline, serotonin, somatostatin, galanin, opioids, cannabinoids, neuropeptide Y on postsynaptic receptors, bound to Gi/0 proteins, should promote LTD of excitatory inputs and LTP of inhibitory inputs. The effect of dopamine, adenosine, acetylcholine, noradrenaline, serotonin, vasopressin, tachykinin, histamine on postsynaptic receptors, bound to Gs and Gq/11 proteins, should oppositively modulate the same inputs. Only synaptically activated excitatory and inhibitory inputs can by influenced by neuromodulators. The character of neuromodulatory influence on modification of hippocampal synaptic efficacy, implying from the suggested mechanism is in accordance with known experimental data.

Animals↗

PubMed2002

[Sacral neuromodulation is effective in the treatment of fecal incontinence with intact sphincter muscles; a prospective study].

OBJECTIVE: To evaluate the therapeutic effect of sacral neuromodulation on faecal incontinence in patients with structurally intact sphincters. DESIGN: Prospective. METHOD: In the period April 1st, 2000 to November 30th, 2001, patients with faecal incontinence and structurally intact sphincters were included, with or without previous surgery, in whom medicinal treatment and biofeedback therapy gave no improvement. Incontinence was defined as involuntary loss of stool at least once a week, which was objectified by completion of a 3-week bowel habit diary. Patients underwent 3 weeks of trial stimulation during which they also kept a diary. The trial stimulation was considered successful if the diary showed a > or = 50% improvement in continence. RESULTS: 38 patients (31 women) with an average age of 54 years (range: 26-73) underwent trial stimulation. Trail stimulation was carried out using a permanent electrode in 6 patients and using peripheral neural evaluation in the remaining 32 patients. Two patients did not respond to peripheral neural evaluation. Upon assessment after the trial stimulation period. continence was found to have improved by > or = 50% in 31 (82%) patients. The number of incontinence episodes decreased by an average of 86% (range: 50-100). In 27 patients an implantable pulse generator was implanted for continuous stimulation. During the average follow-up of 6 months the effect remained satisfactory. Anal manometry during stimulation showed no increase of sphincter pressures. CONCLUSION: Sacral neuromodulation was of therapeutic value in most of the patients treated for faecal incontinence without sphincter damage.

Adult↗

PubMedDate not supplied

[Sacral neuromodulation in fecal continence disorders].

The therapeutic approaches to the impairments of the faecal continence not depending from organic lesions of the anal sphincters or the pelvic floor are often unsuccessful, particularly as far as long distance outcome is concerned. The direct setting to the sacral roots of a magnetic stimulation modulating the reflex activity of the Autonomic Nervous System, firstly applied successfully by the urologist in the bladder incontinence, could correct indefinitely the effects of such a defect implying also a social cost in terms of quality of life and linen clothes expenses. Here details of the Interstim, Medtronic devices are reported, discussing the instrumental and clinical indications and the steps of the protocol of its application, in agreement with the Italian Group of Sacral Neuromodulation (GINS), as well as the most recent data of the literature and the early results of our own experience in the treatment of faecal incontinence. It is stressed the aspect of "work in progress" peculiar to this technique, as clearly shows the difficulty to explain the pathway with which neuromodulation effects on anal sphincters and pelvic floor, and moreover on the colorectal motility, as some ongoing applications to patients with refractory constipation seems to evidence. Data of a long standing follow-up are not yet available but the early and intermediate results are in the main successfully in terms of complete recovery or improvement as clearly show both clinical evidence and subjective evaluation assessing the Quality of Life.

Anal Canal↗

PubMedDate not supplied

Genitourinary applications of sacral neuromodulation.

Sacral neuromodulation provides a new option for the management of voiding dysfunction. For patients with intractable urge-incontinence, interstitial cystitis and non-obstructive urinary retention, this procedure has resulted in significant improvement in urinary frequency, voided volume and pelvic pain. We provide a review of the current literature on sacral neuromodulation and the West Virginia University experience with this procedure.

Electric Stimulation Therapy↗

PubMedDate not supplied

[The influence of neuromodulators on the synaptic plasticity in dopaminergic structures of the midbrain (hypothetical mechanism)].

A mechanism underlying the effects of neuromodulators on long-term changes in the efficacy of excitatory and inhibitory inputs to dopaminergic and inhibitory cells of the substantia nigra and ventral tegmental area is suggested. According to this mechanism, activation of Gi/0 protein-coupled dopamine D2 autoreceptors and opioid kappa (mu) receptors on dopaminergic (inhibitory) cells promotes the LTD of excitatory inputs to these cells and decrease in their activity. Activation of Gq/11 protein-coupled alpha1 adrenoreceptors, muscarinic M1, neurokinin NK3 (alpha1, M3, NK1, serotonin 5-HT2) receptors on dopaminergic (inhibitory) cells as well as activation of Gs protein-coupled D1 receptors on inhibitory cells promotes the LTP of excitatory inputs to these cells and increase in their activity. Augmenting (lowering) GABA release can be provided by activation of presynaptic D1 and M3 receptors (mu, 5-HT1, and adenosine A1) receptors. Increase (decrease) in GABA concentration due to modulation of inhibitory cell activity and/or GABA release will promote the induction of LTD (LTP) of excitatory inputs to target dopamine cells. The model agree with known experimental data describing the involvement of neuromodulators in modification of dopamine cell activity and dopamine release. The suggested model can be useful in understanding the operation of neuronal networks, which include the basal ganglia.

Autoreceptors↗

PubMed2003

Spike timing-dependent serotonergic neuromodulation of synaptic strength intrinsic to a central pattern generator circuit.

Neuromodulation is often thought to have a static, gain-setting function in neural circuits. Here we report a counter example: the neuromodulatory effect of a serotonergic neuron is dependent on the interval between its spikes and those of the neuron being modulated. The serotonergic dorsal swim interneurons (DSIs) are members of the escape swim central pattern generator (CPG) in the mollusk Tritonia diomedea. DSI spike trains heterosynaptically enhanced synaptic potentials evoked by another CPG neuron, ventral swim interneuron B (VSI-B), when VSI-B action potentials occurred within 10 sec of a DSI spike train; however, if VSI-B was stimulated 20-120 sec after DSI, then the amplitude of VSI-B synaptic potentials decreased. Consistent with this, VSI-B-evoked synaptic currents exhibited a temporally biphasic and bidirectional change in amplitude after DSI stimulation. Both the DSI-evoked enhancement and decrement were occluded by serotonin and blocked by the serotonin receptor antagonist methysergide, suggesting that both phases are mediated by serotonin. In most preparations, however, bath-applied serotonin caused only a sustained enhancement of VSI-B synaptic strength. The heterosynaptic modulation interacted with short-term homosynaptic plasticity: DSI-evoked depression was offset by VSI-B homosynaptic facilitation. This caused a complicated temporal pattern of neuromodulation when DSI and VSI-B were stimulated to fire in alternating bursts to mimic the natural motor pattern: DSI strongly enhanced summated VSI-B synaptic potentials and suppressed single synaptic potentials after the cessation of the artificial motor pattern. Thus, spike timing-dependent serotonergic neuromodulatory actions can impart temporal information that may be relevant to the operation of the CPG.

Action Potentials↗

PubMed2004

Parameters of successful sacral root neuromodulation of the pelvic floor: a retrospective study.

INTRODUCTION/OBJECTIVE: Neuromodulation of the pelvic floor (InterStim) is a relatively new technique in the field of urology. We present our observations for effective neuromodulation on our patient population. MATERIALS AND METHODS: In a retrospective case review study, we studied the charts of 67 patients, who underwent InterStim operations between the years 1993 to 2002. All patients had a good response to InterStim. Patients with inefficient or inconclusive responses were not included in the study. All the relevant patient data was recorded from their charts. For each patient, the following was recorded; the amplitude in volts, the pulse width (in microseconds) and rate, the mode (cycling versus continuous), the electrodes and their position, the load impedance, and the change in amplitude over time. RESULTS: Amplitude over time showed an initial plateau, followed by a small increase that gets larger. CONCLUSIONS: Long-term management of InterStim recipients requires increasing amplitude following the implantation of the IntreStim to maintain the same satisfactory levels of urinary control.

Adult↗

PubMed1991

Neurotransmitters and neuromodulators controlling the anterior byssus retractor muscle of Mytilus edulis.

1. The anterior byssus retractor muscle (ABRM) of Mytilus edulis is innervated by at least two kinds of nerves, excitatory and relaxing nerves. The principal neurotransmitters released from these nerves have been shown to be acetylcholine and serotonin, respectively. 2. Some other monoamines, such as dopamine and octopamine, and various peptides, such as FMRFamide-related peptides, Mytilus inhibitory peptides, SCP-related peptides and a catch-relaxing peptide, may also be involved in the regulation of the muscle as neurotransmitters or neuromodulators. 3. The ABRM seems to be typical of invertebrate muscles controlled by multiple neurotransmitters and neuromodulators.

Amino Acid Sequence↗

PubMedDate not supplied

Inhibitory neuromodulation of release of amino acid neurotransmitters.

Many drugs of abuse (opiates, cocaine, amphetamine, caffeine) modulate or interact with neurotransmitter systems in the brain (e.g., opiate, dopaminergic, adrenergic, purinergic), generally in an inhibitory fashion. However the cellular mechanisms underlying these interactions are varied and often not well-characterized. A summary of the literature on the neuromodulation of two amino acid neurotransmitters (gamma-aminobutyric acid, glutamate) by these drugs and their analogs may contribute to the understanding of the mechanisms underlying inhibitory neuromodulation. In addition, the types of experiments needed to alleviate some of the problems in this area are outlined.

Adenosine↗

PubMed1994

Adenosine--an endogenous neuroprotective metabolite and neuromodulator.

Adenosine is now widely accepted as the major inhibitory neuromodulator in the central nervous system besides GABA. It has been suggested to be an endogenous neuroprotective metabolite. In situations of metabolic stress, e.g. ischemia adenosine decreases energy demand and increases energy supply. Of particular relevance in this context is its modulation of glutamate release. A shift of this adenosine-glutamate balance in favor of adenosine helps to restore function at the cellular, organ and organism level. Adenosine A1 receptor agonists and metabolic inhibitors, e.g. of transport, deaminase and xanthine oxidase have been demonstrated to be effective in different animal models of ischemia. Nimodipine, a L-type channel calcium antagonist currently in clinical trials for stroke and dementia syndromes, has now been shown to be a potent adenosine transport inhibitor in clinically relevant concentrations. Increase of adenosinergic neuromodulation may well be one of several future therapeutic strategies in neuroprotection.

Adenosine↗