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PubMed2006

Preliminary results of sacral neuromodulation in 23 children.

PURPOSE: Sacral nerve stimulation with InterStim is approved in the United States for use in adults. Limited data on the effectiveness of sacral nerve stimulation in children are available. We report our experience with patients who underwent InterStim placement for the treatment of severe dysfunctional elimination syndrome, which is defined as a constellation of functional urinary and gastrointestinal symptoms in patients without anatomical anomalies or obvious neurological disease, in whom intensive medical and behavioral therapies have failed to improve symptoms. MATERIALS AND METHODS: A total of 23 patients 6 to 15 years old with presenting symptoms of dysfunctional voiding, enuresis, incontinence, urinary tract infections, bladder pain, urinary retention, urgency, frequency, constipation and/or fecal soiling were followed for a mean of 13.3 months after InterStim placement. RESULTS: Of the 19 patients with urinary incontinence 3 (16%) had complete resolution, 13 (68%) had improvement, 2 (11%) were unchanged and 1 (5%) was worse (sign test, p = 0.002). Among the 16 patients with nocturnal enuresis 2 (13%) had resolution, 9 (56%) improved, 4 (25%) were unchanged and 1 (6%) was worse (sign test, p = 0.0063). Of the 15 patients with urinary retention requiring intervention 9 (60%) had improvement and 1 had worsening symptoms (sign test, p = 0.022), while 2 of 6 patients (33%) on intermittent catheterization were able to stop. One patient had development of new incontinence and enuresis. Bladder pain, urgency, frequency and constipation improved in 67% (8 of 12), 75% (12 of 16), 73% (11 of 15) and 80% (12 of 15) of the patients, respectively. Medications required postoperatively decreased by an average of 3 per patient (p < 0.001). The overall patient satisfaction rate was 64%, while that of the caregiver was 67%. Two leads were explanted from the 23 patients. Complications encountered included 1 seroma, 1 episode of skin sensitivity, 2 device failures and 1 lead revision. CONCLUSIONS: Sacral nerve stimulation in children is an option for carefully selected patients who have failed other therapies. Our results show that sacral nerve stimulation was effective in the majority of patients with the dysfunctional elimination syndrome. However, longer followup is needed.

Child↗
PubMed2005

Neuropharmacology of cognition and memory: a unifying theory of neuromodulator imbalance in psychiatry and amnesia.

The case of HM, a man with intractable epilepsy who became amnesic following bilateral medial temporal lobe surgery nearly half a century ago has instigated ongoing research and theoretical speculation on the nature of memory and the role of the hippocampus. Neuropsychological testing showed that although HM had extensive anterograde memory loss he could still acquire motor and cognitive skills implicitly, but could not remember the context of this learning. This has lead to declarative and procedural descriptions of the memory process. Cholinergic and monoaminergic neurotransmitter systems have also been implicated in the memory process and anticholinergic drugs traditionally have been associated with impairment of declarative memory. The cholinergic hypothesis of Alzheimer's disease is a classic example of an application of these neuropharmacological findings. In schizophrenia, preattentive deficits have been amply demonstrated by unconscious priming studies. Memory processes are also impaired in these patients. Dopamine, glutamate and even cholinergic dysfunction has been implicated in the clinical picture of schizophrenia. The present paper will attempt to bring together both the anatomical and pharmacological data from these disparate fields of research under a cohesive theory of cognition and memory. A hypothesis is presented for an inverse relationship between monoaminergic and cholinergic systems in the modulation of implicit (unconscious) and explicit (conscious) cognitive processes. It is postulated that muscarinic cholinergic receptors and monoaminergic systems facilitate unconscious and conscious processes, respectively, and they disfacilitate conscious and unconscious processes, respectively (the purported inverse relationship). In fact, the muscarinic and monoaminergic modulations of a neural network are proposed to be finely balanced such that, if, the activity of one receptor system is modified then this by necessity has effects on the other system. It takes into account receptor subtypes and their effects mediated through excitatory and inhibitory G-protein complexes. For example, m1/D2 and D1/m4 paired receptor subtypes, colocalized on separate neurons would have opposing functional effects. A theory is then presented that the critical underlying pathophysiology of schizophrenia involves a hypofunctional muscarinic cholinergic system, which induces abnormal facilitation of monoaminergic subsystems such as dopamine (e.g., a decrease in m1R function would potentiate D2R function). This extends the idea of an inverted U function for optimal monoaminergic concentrations. Not only would this impair unconscious preattentive processes, but according to the hypothesis, explicit cognition as well including memory deficits and would underlie the mechanism of psychosis. Contrary to current thinking a different view is also presented for the role of the hippocampus in the memory process. It is postulated that long-term explicit memory traces in the neocortex are laid down by phasic coactivation of forebrain projecting monoaminergic systems above some basal firing rate, such as the rostral serotonergic raphe, which projects diffusely to the cortex and according to a modified Hebbian principle. This is the proposed principal function of the hippocampal theta rhythm. The phasic activation of the cholinergic basal forebrain is mediated by projections from a separate cortical structure, possibly the lateral prefrontal cortex. Phasic muscarinic receptor activation is proposed to strengthen implicit memory traces (at a synaptic level) in the neocortex. Thus, the latter are spared by medial temporal surgery explaining the dissociation of explicit from implicit memory.

Amnesia↗
PubMed2004

Neuromodulation of experimental Shigella infection reduces damage to the gut mucosa.

Bacillary dysentery arises when Shigella invades the colonic and rectal mucosae of the human gut and elicits a strong inflammatory response, which may lead to life-threatening complications. Hence, downregulation of the host inflammatory response is an appealing therapeutical alternative. The gastrointestinal tract is densely innervated, and nerve endings are often found in the vicinity of leukocytes. We have assessed the impact of experimental Shigella infection on levels of neuropeptides in the intestinal mucosa of rabbits. Ligated small intestinal loops were created in rabbits, and either live, pathogenic Shigella flexneri, a nonpathogenic mutant of Shigella, or NaCl was injected into the loops. Infection was allowed to proceed for 8 or 16 h, after which the rabbits were sacrificed and intestinal biopsies collected. Tissue destruction, fluid secretion and degree of bacterial invasion were monitored. Intestinal biopsies were homogenized, and levels of the neuropeptides calcitonin gene-related peptide, substance P, peptide YY (PYY), vasoactive intestinal peptide, somatostatin, galanin, motilin and neurotensin were measured by radioimmunoassay. Loops exposed to invasive Shigella had 5.7 times lower levels of PYY (P = 0.0095) than loops exposed to NaCl, after 16 h of infection. The levels of the other neuropeptides tested were unchanged. Inhibition of nicotinic cholinergic neurotransmission partly protected the intestinal mucosa from destruction elicited by invasive Shigella. These findings indicate that a tissue-invasive bacterium such as Shigella, which is strictly localized to the intestinal mucosa, activates intramural nerve reflexes that presumably involve a nicotinic synapse as well as the neuropeptide PYY.

Animals↗
PubMed2005

Inhibitory effect of gaseous neuromodulators in vasopressin and oxytocin release induced by endotoxin in rats.

Nitric oxide (NO) and carbon monoxide (CO) are endogenously synthesized gaseous molecules that act as neurotransmitters in central nervous system. In this study we investigated the modulatory role of NO and CO in lipopolysaccharide (LPS)-induced vasopressin and oxytocin secretion. Intracerebroventricular (i.c.v.) injection of N omega-L-nitro-arginine methyl ester (L-NAME), 3-morpholino-sydnonimine (SIN-1), zinc deuteroporphyrin 2,4-bis glicol (ZnDPBG) or hemin did not change the basal vasopressin and oxytocin plasma levels. After endovenous LPS administration, plasma vasopressin and oxytocin increased, reaching a peak at 60 min, and returning to basal levels afterwards. LPS administration induced a higher vasopressin and oxytocin plasma levels in rats previously treated with L-NAME and ZnDPBG (P<0.05) compared to rats pre-treated with vehicle. On the other hand, in rats previously treated with SIN-1 or hemin, there was a significant reduction in the vasopressin and oxytocin secretion. These findings confirm the inhibitory role of NO and CO in the LPS-induced vasopressin and oxytocin secretion.

Animals↗
PubMed2005

Neuromodulation via conditional release of endocannabinoids in the spinal locomotor network.

Endocannabinoids act as retrograde signals to modulate synaptic transmission. Little is known, however, about their significance in integrated network activity underlying motor behavior. We have examined the physiological effects of endocannabinoids in a neuronal network underlying locomotor behavior using the isolated lamprey spinal cord. Our results show that endocannabinoids are released during locomotor activity and participate in setting the baseline burst rate. They are released in response to mGluR1 activation and act as retrograde messengers. This conditional release of endocannabinoids can transform motoneurons and crossing interneurons into modulatory neurons by enabling them to regulate their inhibitory synaptic inputs and thus contribute to the modulation of the locomotor burst frequency. These results provide evidence that endocannabinoid retrograde signaling occurs within the locomotor network and contributes to motor pattern generation and regulation in the spinal cord.

Action Potentials↗
PubMed2005

Expecting the unexpected: modeling of neuromodulation.

An important aspect of decision-making is the need to make interpretations and predictions in the face of uncertain information. In this issue of Neuron, Yu and Dayan describe a model of the role of acetylcholine and norepinephrine in balancing top-down expectation and bottom-up sensory input in guiding behavior. The model builds from data on physiological effects of modulators regulating the balance of cortical feedback and thalamic input.

Acetylcholine↗
PubMed2006

The mysterious trace amines: protean neuromodulators of synaptic transmission in mammalian brain.

The trace amines are a structurally related group of amines and their isomers synthesized in mammalian brain and peripheral nervous tissues. They are closely associated metabolically with the dopamine, noradrenaline and serotonin neurotransmitter systems in mammalian brain. Like dopamine, noradrenaline and serotonin the trace amines have been implicated in a vast array of human disorders of affect and cognition. The trace amines are unique as they are present in trace concentrations, exhibit high rates of metabolism and are distributed heterogeneously in mammalian brain. While some are synthesized in their parent amine neurotransmitter systems, there is also evidence to suggest other trace amines may comprise their own independent neurotransmitter systems. A substantial body of evidence suggests that the trace amines may play very significant roles in the coordination of biogenic amine-based synaptic physiology. At high concentrations, they have well-characterized presynaptic "amphetamine-like" effects on catecholamine and indolamine release, reuptake and biosynthesis; at lower concentrations, they possess postsynaptic modulatory effects that potentiate the activity of other neurotransmitters, particularly dopamine and serotonin. The trace amines also possess electrophysiological effects that are in opposition to these neurotransmitters, indicating to some researchers the existence of receptors specific for the trace amines. While binding sites or receptors for a few of the trace amines have been advanced, the absence of cloned receptor protein has impeded significant development of their detailed mechanistic roles in the coordination of catecholamine and indolamine synaptic physiology. The recent discovery and characterization of a family of mammalian G protein-coupled receptors responsive to trace amines such as beta-phenylethylamine, tyramine, and octopamine, including socially ingested psychotropic drugs such as amphetamine, 3,4-methylenedioxymethamphetamine, N,N-dimethyltryptamine, and lysergic acid diethylamide, have revitalized the field of scientific studies investigating trace amine synaptic physiology, and its association with major human disorders of affect and cognition.

Amines↗
PubMedDate not supplied

Subcutaneous neuromodulating implant targeted at the site of pain.

INTRODUCTION: Primary afferent stimulation for the control of chronic pain frequently offers the optimal compromise for the control of intractable pain. We describe a new access route directly to the site of pain (target) in the form of subcutaneous targeted neurostimulation (STN) via a percutaneous permanent neurostimulating implant. CASE REPORT: We present 3 cases with chronic intractable pain where STN via a permanent neurostimulating implant was introduced successfully. STN for 1-2 hours daily produced pain relief lasting between 12 to 24 hours, which argues that subcutaneous neurostimulation instead of stimulation of peripheral nerves is sufficient in selected cases. The effects of subcutaneous stimulation do not correlate with transcutaneous electrical nerve stimulation applied externally over the same area. CONCLUSION: The introduction of an STN directly to painful areas, therefore bypassing the spinal cord and peripheral nerves, is a novel and simple procedure that is effective, in this small series, for control of intractable pain consistent with neuropathic pain.

Adult↗
PubMed2005

Neuromodulation in pediatrics.

Several neuromodulatory options are available for selected children who have voiding dysfunction resistant to conventional therapy. Integral to all types of treatment is an educated team that reinforces progress rather than cure and encourages long-term behavioral changes.

Child↗
PubMed2005

How sacral nerve stimulation neuromodulation works.

The authors believe that the principles underlying the multiple possible SNS mechanisms of action can be summarized as somatic afferent inhibition of sensory processing in the spinal cord. Regardless of whether the lower urinary tract dysfunction involves storage versus emptying abnormalities, the pudendal afferent signaling serves as a common crossroads in the neurologic wiring of the system. Not only can pudendal afferent input turn on voiding reflexes by sup-pressing the guarding reflex pathways, pudendal afferent input to the sacral spinal cord also can turn off supraspinally mediated hyperactive voiding by blocking ascending sensory pathway inputs. For these reasons, SNS can take advantage of the complex neurologic pathways described and offer successful treatment for a seemingly disparate group of lower urinary tract pathologies. SNS is a urologic technique that has proved safe and minimally invasive, and it holds great promise for many patients who have lower urinary tract dysfunction.

Afferent Pathways↗
PubMed2005

Neuromodulation for constipation and fecal incontinence.

The evidence is consistent with permanent SNM substantially improving continence in patients with severe fecal incontinence resistant to medical treatment. This treatment has been used in patients in whom a major surgical intervention would normally have been the next stage in treatment and the option of a minimally invasive treatment, with the added advantage of testing before definitive implantation, has the potential to have a major impact on this patient group. The results of the early case series examining the use of SNM for constipation are encouraging. Patients who have failed maximal medical treatment for constipation pose considerable clinical difficulties, with current surgical treatments requiring a bowel resection or stoma formation. If SNM proves to be of benefit to a proportion of these patients, this will be of considerable importance in terms of their future treatment options. Fecal incontinence and idiopathic constipation are both conditions in which conservative treatment is the mainstay of treatment in most cases,but for a small proportion surgical intervention is warranted. The surgical procedures available,however, have a considerable invasive component with often little guarantee of symptom resolution. SNM is becoming more widely used for patients with fecal incontinence as series sizes get larger and follow-up longer. Its potential benefit in constipation has been shown in pilot studies but larger trials are still required.

Constipation↗
PubMed2005

Future directions in pelvic neuromodulation.

In view of the success of sacral nerve stimulation, new lines of research are enabling us to do more selective stimulation of the innervation of the bladder at more peripheral sites,such as pudendal nerve stimulation, and with the use of less invasive devices, such as Bion and other in situ implantable devices. The aim of this research is to determine ifa less invasive, more selective stimulation or an event-driven (detrusor overactivity ora desire for micturition) stimulus would allow for a more improved and durable response.

Botulinum Toxins, Type A↗
PubMed2003

Mitochondrial uncoupling protein 2 in the central nervous system: neuromodulator and neuroprotector.

Uncoupling proteins (UCPs) are localized in the inner membrane of the mitochondria in diverse tissues and decrease mitochondrial membrane potential. The first of these proteins, UCP1, was discovered in brown adipose tissue, where it has a well-described role in thermogenesis. The functional significance of other UCPs, including UCP2, is less well understood. Here we summarize the recent advancements on the role of UCP2 in the brain and portray this uncoupler as an important player in normal neuronal function as well as a key cell death-suppressing device. These previously unknown functions of UCPs offer new avenues not only for the better understanding of these proteins but also for the furthering of our knowledge on the central nervous system in healthy and disease states.

Animals↗
PubMed2000

Polycyclic neuromodulation of the feeding rhythm of the pond snail Lymnaea stagnalis by the intrinsic octopaminergic interneuron, OC.

We have examined the role of the octopamine-containing buccal OC interneuron in the fictive feeding rhythm generated by depolarizing a modulatory interneuron, SO, in the isolated central nervous system (CNS) of Lymnaea stagnalis. Before stimulating the SO, the initial fictive feeding rate was 2.0+/-0.37 bites/min (mean+/-S.E.). When the SO was stimulated, the fictive feeding rate more than doubled, increasing by 5.4+/-2.6 bites/min. Prestimulation of OC facilitates the ability of the modulatory neuron SO to drive fictive feeding 4 s later. Following OC stimulation, the increase in SO-driven feeding rate was 10.8+/-1.6 bites/min, significantly more than when only the SO was stimulated (P<0.02, paired t-test on five preparations). OC activity is not required during the SO stimulation for this enhancement. The maximum of the SO driven rhythm occurs between 6 and 12 s after the end of the OC stimulation at 20 bites/min. This is the maximum feeding rate of intact Lymnaea in sucrose. Facilitation is mimicked by bath applied octopamine at 5 microM. Facilitation is specific to OC interneurons, as the same prestimulation of the electrically coupled neuron N3P (central pattern generator) interneurons does not affect the feeding rhythm. The OC interneuron acts as a long term, polycyclic modulator, which peaks several feeding cycles after the OC activity.

Adrenergic alpha-Agonists↗
PubMed2002

Glial transport of the neuromodulator D-serine.

D-Serine is an endogenous agonist of NMDA receptors that occurs in astrocytes in gray matter areas of the brain. D-Serine is synthesized from L-serine by the activity of a glial enriched serine racemase, but little is known on the properties of D-serine transport and factors regulating its synaptic concentration. In the present report we characterize the transport of D-serine in astrocytes. In primary astrocyte cultures, D-serine uptake is dependent on sodium ions and exhibits both low affinity and low specificity for D-serine. The kinetics of D-serine transport resembles that of ASCT type transporters as several small neutral amino acids strongly inhibit the uptake of D-serine. D-Serine fluxes are coupled to counter-movement of L-serine and to a less extent to other small neutral amino acids. Thus, addition of D-serine to cell cultures elicits robust efflux of intracellular L-serine. Conversely, physiological concentrations of L-serine induce efflux of preloaded D-serine from astrocytes. L-Serine was more effective than kainate, which have been previously shown to induce D-serine release from astrocytes upon stimulation of non-NMDA type of glutamate receptors. The features of D-serine transport we describe reveal possible new mechanisms controlling the synaptic concentration of D-serine.

Amino Acids, Neutral↗
PubMed1997

Estrogen as a neuromodulator of MPTP-induced neurotoxicity: effects upon striatal dopamine release.

The effects of estrogen upon MPTP-induced neurotoxicity were examined using in vitro superfusion. In Experiment 1, striatal tissue from ovariectomized rats was infused with MPP+ (10 microM), a combination of MPP+ and 17beta-estradiol (300 nM), the same dose of estradiol preceding MPP+, or no treatment infusion. The effects of these treatments on dopamine release rates during the infusion periods were determined. Infusion of MPP+ resulted in a significant increase in dopamine release as compared to the control. Estradiol added to the MPP+ infusion significantly attenuated this dopamine (DA) release, while estradiol treatment preceding the MPP+ had no effect. In Experiment 2, three different doses of estradiol (0.3, 3, or 300 nM) were infused simultaneously with the MPP+. Doses of estradiol below 300 nM did not attenuate the DA release. In Experiment 3, estradiol alone (300 nM) was infused, to determine dopamine release rate effects of the hormone itself. There was no difference between estradiol treated and non-infused control groups. These results demonstrate that the gonadal steroid hormone estradiol can modulate responses of striatal dopamine neurons to MPP+ by altering the immediate increase in dopamine release which occurs in response to this neurotoxin. These modulating effects of estradiol are dose-dependent, and represent a direct effect upon striatal neurons, most likely involving a non-genomic mechanism of action. These results implicate that hormonal modulation of nigrostriatal dopaminergic neurotoxicity may represent an important variable responsible for the sex differences which are reported in Parkinson's disease.

1-Methyl-4-phenylpyridinium↗