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PubMed2006

Neuromodulation of associative and organizational plasticity across the life span: empirical evidence and neurocomputational modeling.

Developmental plasticity is the key mechanism that allows humans and other organisms to modify and adapt to contextual and experiential influences. Thus, reciprocal co-constructive interactions between behavioral and neuronal plasticity play important roles in regulating neurobehavioral development across the life span. This review focuses on behavioral and neuronal evidence of lifespan differences in associative memory plasticity and plasticity of the functional organization of cognitive and cortical processes, as well as the role of the dopaminergic system in modulating such plasticity. Special attention is given to neurocomputational models that help exploring lifespan differences in neuromodulation of neuronal and behavioral plasticity. Simulation results from these models suggest that lifespan changes in the efficacy of neuromodulatory mechanisms may shape associative memory plasticity and the functional organization of neurocognitive processes by affecting the fidelity of neuronal signal transmission, which has consequences for the distinctiveness of neurocognitive representations and the efficacy of distributed neural coding.

Animals↗

PubMed2006

Sulfated steroids as endogenous neuromodulators.

Central nervous system function is critically dependent upon an exquisitely tuned balance between excitatory synaptic transmission, mediated primarily by glutamate, and inhibitory synaptic transmission, mediated primarily by GABA. Modulation of either excitation or inhibition would be expected to result in altered functionality of finely tuned synaptic pathways and global neural systems, leading to altered nervous system function. Administration of positive or negative modulators of ligand-gated ion channels has been used extensively and successfully in CNS therapeutics, particularly for the induction of sedation and treatment of anxiety, seizures, insomnia, and pain. Excessive activation of excitatory glutamate receptors, such as in cerebral ischemia, can result in neuronal damage via excitotoxic mechanisms. The discovery that neuroactive steroids exert rapid, direct effects upon the function of both excitatory and inhibitory neurotransmitter receptors has raised the possibility that endogenous neurosteroids may play a regulatory role in synaptic transmission by modulating the balance between excitatory and inhibitory neurotransmission. The sites to which neuroactive steroids bind may also serve as targets for the discovery of therapeutic neuromodulators.

Animals↗

PubMed2004

Regulation of neuromodulator receptor efficacy--implications for whole-neuron and synaptic plasticity.

Membrane receptors for neuromodulators (NM) are highly regulated in their distribution and efficacy-a phenomenon which influences the individual cell's response to central signals of NM release. Even though NM receptor regulation is implicated in the pharmacological action of many drugs, and is also known to be influenced by various environmental factors, its functional consequences and modes of action are not well understood. In this paper we summarize relevant experimental evidence on NM receptor regulation (specifically dopamine D1 and D2 receptors) in order to explore its significance for neural and synaptic plasticity. We identify the relevant components of NM receptor regulation (receptor phosphorylation, receptor trafficking and sensitization of second-messenger pathways) gained from studies on cultured cells. Key principles in the regulation and control of short-term plasticity (sensitization) are identified, and a model is presented which employs direct and indirect feedback regulation of receptor efficacy. We also discuss long-term plasticity which involves shifts in receptor sensitivity and loss of responsivity to NM signals. Finally, we discuss the implications of NM receptor regulation for models of brain plasticity and memorization. We emphasize that a realistic model of brain plasticity will have to go beyond Hebbian models of long-term potentiation and depression. Plasticity in the distribution and efficacy of NM receptors may provide another important source of functional plasticity with implications for learning and memory.

Animals↗

PubMed2005

The bion device: a minimally invasive implantable ministimulator for pudendal nerve neuromodulation in patients with detrusor overactivity incontinence.

The results of the bion pilot studies indicate that a considerable reduction in the degree of detrusor overactivity incontinence can be obtained in severely refractory cases, including women who had failed sacral nerve neuromodulation. The described technique is well tolerated by the patients. It is minimally invasive and relatively simple. Clinical trials of the bion-r device involving larger numbers of patients are underway in the United States and Europe. A subchronic instead of the currently used acute screening test might increase the percentage of patients assessed as suitable candidates for implantation. There-fore, methods of performing a subchronic test of the pudendal nerve also are being investigated.

Electric Stimulation Therapy↗

PubMed2005

Percutaneous neuromodulation.

Neuromodulation for pelvic floor dysfunction has evolved from central sacral stimulation, a relatively invasive, experimental procedure, to percutaneous peripheral neurostimulation, which is both minimally invasive and well-tolerated by patients. Multiple series have now reported consistent positive results for varied manifestations of pelvic floor dysfunction. Future applications will involve an implantable peripheral neurostimulator coupling with the posterior tibial nerve, empowering patients to adjust the frequency or amplitude of stimulation. It is anticipated that broader availability of this modality will offer hope to the frequently underdiagnosed and underreported population of patients with pelvic floor dysfunction.

Electric Stimulation Therapy↗

PubMed2005

European experience with bilateral sacral neuromodulation in patients with chronic lower urinary tract dysfunction.

Although there is experimental and clinical evidence that bilateral stimulation of the sacral nerves could lead to summation effects, no significant differences in unilateral versus bilateral neuromodulation could be demonstrated in a comparative trial. In some individuals, however, only bilateral stimulation relieved symptoms. Therefore, if a unilateral percutaneous nerve evaluation test fails, a bilateral test should be considered. Further clinical research with long-term follow-up will allow the identification of which patients could benefit from bilateral stimulation with greater specificity and ameliorate further the long-term results achieved with unilateral SNS.

Electric Stimulation Therapy↗

PubMed2005

Canadian experience in sacral neuromodulation.

The application of sacral nerve modulation and stimulation has gained wide acceptance asa tool to enhance the control of voiding. The simplicity of the technique has made the therapy appealing for refractory cases of voiding dysfunction. The percutaneous screening test is mandatory for the success of the therapy. Long-term follow-ups have shown efficacy and safety inpatients with voiding dysfunction. Sacral nerve modulation is an effective modality in the treatment of various voiding and storage dysfunction. The tined lead offers a minimally invasive implant procedure. The simplicity of the procedure and the patient's sensory awareness help to ensure best lead placement. Furthermore, local anesthesia instead of general anesthesia allows faster patient recovery and reduces complications. Finally, sacral neuromodulation offers a modality in the management of patients with voiding dysfunction.

Adult↗

PubMed2006

Evaluation and management of malfunctioning sacral neuromodulator.

OBJECTIVES: To describe a strategy for revising the malfunctioning InterStim device and to provide an algorithm for evaluation and management. METHODS: We retrospectively reviewed 82 patients who had undergone InterStim placement. Ten patients (eight women and two men) experienced complications and subsequently underwent revision of their device between October 2001 and October 2003. Five patients had originally received a permanent implant after a successful percutaneous test stimulation trial, and five had undergone a test stimulation using the tined lead. Indications for revision included gradual onset of recurrent voiding dysfunction (n = 2), lead migration (n = 5), generator malfunction (n = 1), generator site pain and infection (n = 1), and genital/rectal pain with stimulation (sensory discomfort; n = 1). RESULTS: Of the 10 patients who underwent revision, 7 experienced complete resolution of their problem. Eight patients had lead site changes and two had generator replacements. No intraoperative or postoperative complications occurred in the revision cases. CONCLUSIONS: In our experience, 70% of patients who undergo revision of the malfunctioning InterStim can expect success. In this study, no difference in success appeared to be related to the original cause of malfunction. In the management of malfunctioning sacral neuromodulators, we recommend an attempt at revision before permanent explantation.

Algorithms↗

PubMed1999

Importance of stimulation paradigm in determining facilitation and effects of neuromodulation.

Evoked synaptic activity within the CNS and at the neuromuscular junction in most in vivo preparations studied occurs not with single isolated stimuli, but with trains, or bursts, of stimuli. Although for ease in studying the mechanisms of vesicular synaptic transmission one often uses single discrete stimuli, the true mechanisms in the animal may be far more complex. When repetitive stimuli are present at a nerve terminal, often a heightened (i.e., facilitated) postsynaptic potential can be as a result. Facilitation is commonly used as an index of synaptic function and plasticity induced by chronic stimulation or by neuromodulation. The mechanisms that give rise to facilitation are thought to be the same that may underlie short-term learning and memory [C.H. Bailey, E.R. Kandel, Structural changes accompanying memory storage. Annu. Rev. Physiol. 55 (1993) 397-426.]. Differences in short term facilitation (STF) are seen depending on the conventional stimulation paradigm (twin pulse, train, or continuous) used to induce facilitation. Thus, a battery of paradigms should be used to characterize synaptic function to obtain a closer understanding of the possible in vivo conditions.

Animals↗

PubMed1997

Evidence against nitrergic neuromodulation in the rat vas deferens.

Electrical field stimulation (60 V, 1 ms, single pulses or 20 s trains of 1-10 Hz) of the nerve terminals within the rat vas deferens produced biphasic contractions in preparations oriented to measure either longitudinal or circular muscle contractions. In confirmation of earlier reports, these contractions were blocked by tetrodotoxin (1 microM). The initial fast purinergic contraction was dominant in prostatic halves of the vas deferens while the second slower noradrenergic contraction was greater in epididymal halves. Although previous studies have shown nitric oxide synthase immuno-positive nerves in the vas deferens, electrical field stimulation-induced contractions were unaffected by L-arginine, sodium nitroprusside, N-nitro-L-arginine methyl ester (L-NAME) or superoxide dismutase in concentrations up to I mM. In concentrations above 1 mM, L-NAME reduced the size of the field stimulation-induced contractions but this effect could not be reversed by either L-arginine or sodium nitroprusside. Furthermore, L-arginine, sodium nitroprusside and L-NAME did not affect the contractions induced by exogenous application of noradrenaline (10 microM), ATP (1 mM) or BaCl2 (1-10 mM). We conclude that nitric oxide does not act as a neuromodulator in isolated preparations of rat vas deferens.

Animals↗

PubMed1999

Adenosine A2A receptor interactions with receptors for other neurotransmitters and neuromodulators.

Adenosine, by activating adenosine A2A receptors, seems to have a crucial function in regulating the activation of multiple receptors that affect neurotransmitter release and/or synaptic transmission, in particular receptors for neuropeptides (calcitonin gene related peptide (CGRP) and vasoactive intestinal peptide (VIP)), and NMDA receptors, metabotropic glutamate receptors, nicotinic autofacilitatory receptors, dopamine receptors and adenosine A1 receptors. The manner in which these A2A receptors are involved in interactions with the receptors for other neurotransmitters and or neuromodulators opens novel avenues for the action of this 'omnipresent' nucleoside. Either by direct receptor-receptor modulation or by post-receptor mechanisms, adenosine, in its 'obsession' to protect cells from insults, uses as many receptor systems as possible to synchronize synaptic transmission, in order to exert what seems to be the 'destiny' of this nucleoside--protection of the nervous system.

Adenosine↗

PubMed1991

Short-term facilitation as a tool to know neuromodulator-induced change in Ca2+ movement in the nerve terminal.

A theory was developed to show how we can predict the actions of neuromodulators on Ca2+ movement (yo: impulse-induced increase in Ca2+ concentration; c: basal Ca2+ level) in the nerve terminal from their effects on an impulse-evoked transmitter release (m: quantal content) and short-term facilitation (F) elicited by paired impulses, based on the simplest version of the residual Ca2+ hypothesis of facilitation. It was demonstrated from this theory that yo should be increased (decreased) when both m and F were increased (decreased) and that c should be increased (decreased) when m and F were increased (decreased) and decreased (increased), respectively. These ideas could interpret some published experimental results well.

Animals↗

PubMed1999

Biosynthesis and inactivation of endocannabinoids: relevance to their proposed role as neuromodulators.

The two putative endogenous ligands of cannabinoid receptors, anandamide and 2-arachidonoylglycerol, are synthesized by and released from neurons in a Ca2+-dependent fashion, and re-uptaken and catabolized by both neurons and astrocytes. These biochemical features of the endocannabinoids, as well as some of their pharmacological effects in both central and peripheral nervous systems, suggest a role as neuromodulators for these metabolites. This neuromodulatory role is supported by the brain regional distribution of anandamide, its biosynthetic precursor and its major inactivating enzyme, and by the existence of possible regulatory mechanisms for the biosynthesis and inactivation of endocannabinoids, which are reviewed in this article.

Animals↗

PubMed2001

Modified techniques of S3 foramen localization and lead implantation in S3 neuromodulation.

INTRODUCTION: We describe a reproducible and less invasive surgical approach to sacral neuromodulation (InterStim Therapy) in the treatment of voiding dysfunction. Twenty patients underwent modified lead implantation (mean operative time 45 minutes) without any difficulties or complications, with a mean follow-up of 8 months (range 1 to 14).Technical Considerations. The highlights of these modifications include (a) fluoroscopy to localize the S3 foramen; (b) paramedian incision; (c) use of a cutoff S3 finder needle and a 14-gauge Angiocath to direct permanent lead into the S3 foramen without dissection; (d) use of lateral fluoroscopy to determine the depth of the Angiocath insertion; and (e) anchoring the lead to the lumbodorsal fascia (superficial to the sacral periosteum) using a moveable lead anchor system. These modifications simplify and minimize the invasiveness of this therapy without compromising the efficacy. CONCLUSIONS: Because of the simplicity of these modifications, we are currently using an implanted lead, rather than the temporary percutaneous lead, to assess patients' clinical response before implanting a pulse generator.

Electric Stimulation Therapy↗

PubMed2002

Predictive factors for sacral neuromodulation in chronic lower urinary tract dysfunction.

OBJECTIVES: To investigate data from 211 patients who underwent a trial stimulation (percutaneous nerve evaluation [PNE]) to determine the clinical parameters that can enhance the prediction of PNE success. The advantageous effect of sacral neuromodulation depends on the accurate identification of suitable candidates during the preimplantation PNE. METHODS: A total of 211 patients (161 women and 50 men), with refractory urge incontinence, urgency-frequency syndrome, and urinary retention, underwent a PNE. Patient data (demographics, medical history, urologic investigations, and diagnosis) were collected. The PNE results were evaluated from a voiding diary and patient history. More than 50% improvement of voiding parameters was considered a successful PNE, and those patients were selected for implantation. Logistic regression analysis was performed. The factors tested for predicting the test result were sex, patient age, diagnosis, previous surgery, neurogenic bladder dysfunction, duration of complaints, and previous treatments. RESULTS: The PNEs were positive in 85 patients (40.3%) and negative in 105 patients (49.8%). In 18 patients (8.5%), the test electrode had migrated; 3 more patients were not assessable and were also excluded. Missing data on the variable "duration of complaints" reduced the number of patients in the analyses from 190 to 174 patients. CONCLUSIONS: Intervertebral disk prolapse, duration of complaints, neurogenic bladder dysfunction, and urge incontinence were found to be significant predictive factors. However, a PNE remains necessary to evaluate a patient's chance of implant success objectively.

Adult↗

PubMed1997

Improving neuromodulation technique for refractory voiding dysfunctions: two-stage implant.

OBJECTIVES: Neuromodulation is a new technique that uses electrical stimulation of the sacral nerves for patients with refractory urinary urge/frequency or urge-incontinence, and some forms of urinary retention. The limiting factor for receiving an implant is often a failure of the percutaneous nerve evaluation (PNE) test. Present publications mention only about a 50% success score for PNE of all patients, although the micturition diaries and urodynamic parameters are similar. We wanted to investigate whether PNE results improved by using a permanent electrode as a PNE test. This would show that improvement of the PNE technique is feasible. METHODS: In 10 patients where the original PNE had failed to improve the micturition diary parameters more than 50%, a permanent electrode was implanted by operation. It was connected to an external stimulator. In those cases where the patients improved according to their micturition diary by more than 50% during a period of 4 days, the external stimulator was replaced by a permanent subcutaneous neurostimulator. RESULTS: Eight of the 10 patients had a good to very good result (60% to 90% improvement) during the testing period and received their implant 5 to 14 days after the first stage. CONCLUSIONS: The good results of the two-stage implant technique we used indicate that the development of better PNE electrodes may lead to an improvement of the testing technique and better selection between nonresponders and technical failures.

Adult↗

PubMed1997

Tumor necrosis factor-alpha: a neuromodulator in the CNS.

In the central nervous system (CNS), the cytokine tumor necrosis factor-alpha (TNF alpha) is produced by both neurons and glial cells, participates in developmental modeling, and is involved in many pathophysiological conditions. There are activity-dependent expressions of TNF alpha as well as low levels of secretion in the resting state. In contrast to the conventional view of a cytotoxic effect of TNF alpha, accumulating evidence suggests a beneficial effect when TNF alpha is applied at optimal doses and at specific periods of time. The bimodal effect is related to subtypes of receptors, activation of different signal transduction pathways, and the presence of other molecules that alter the intracellular response elements such as immediate-early genes. TNF alpha may be an important neuromodulator in development of the CNS, diseases of demyelination and degeneration, and in the process of regeneration. It could induce growth-promoting cytokines and neurotrophins, or it could increase the production of antiproliferative cytokines, nitric oxide, and free radicals, thereby contributing to apoptosis.

Animals↗

PubMed2002

Fast inhibitory synapses: targets for neuromodulation and development of vertebrate motor behaviour.

Locomotor networks must possess the inherent flexibility to adapt their output. In this review we discuss evidence from a simple vertebrate locomotor network that suggests fast inhibitory synapses are important targets for the forms of neuromodulation that afford this flexibility. Two important inhibitory transmitters, glycine and GABA, are present in the CNS of Xenopus tadpoles, where they each play distinct roles in the control of swimming. Glycine, but not GABA, contributes to the inhibitory mid-cycle component of each swim-cycle, the strength of which determines the frequency of swimming. Meanwhile, GABA release onto the swim network prematurely terminates swimming episodes. Hence, glycine controls how fast, whilst GABA controls how far the tadpole swims. Our work has focused on how the amines serotonin (5-HT) and noradrenaline (NA), and more recently the gas nitric oxide (NO), selectively target glycine and GABA release in the spinal cord to modulate swimming. In particular, we have identified three brainstem populations of nitrergic neurons, which suggests that nitric oxide may co-localise with 5-HT, NA and GABA. Here we review this work and suggest a hierarchy of brainstem modulatory systems, with NO acting as a metamodulator.

Animals↗