Sharp-Wave Ripple Frequency and Interictal Epileptic Discharges Increase in Tandem During Thermal Induction of Seizures in a Mouse Model of Genetic Epilepsy.

Dravet Syndrome (DS) is a genetic, infantile-onset epilepsy with refractory seizures and severe cognitive impairment. While network level pathophysiology is poorly understood, work in genetic mouse models of DS reveals selective reduction of inhibitory interneuron excitability, a likely mechanism of seizures and comorbidities. Consistent with the critical role of interneurons in timing and recruitment of network activity, hippocampal sharp wave ripples (SPW-R)-interneuron dependent compound brain rhythms essential for spatial learning and memory-are less frequent and ripple frequency is slower in DS mice, both likely to impair cognitive performance. Febrile seizures are characteristic of DS, reflecting a temperature-dependent shift in excitation-inhibition balance. DS interneurons are sensitive to depolarization block and may fall silent with increased excitation precipitating epileptic transformation of ripples. To determine the temperature dependence of SWP-R features and relationship of SPW-R to hippocampal interictal activity, we recorded hippocampal local field potentials in a DS mouse model and wildtype littermate controls while increasing core body temperature. In both genotypes, temperature elevation speeds ripple frequency, although DS ripples remain consistently slower. The rate of SPW-R also increases in both genotypes but subsequently falls in DS mice as interictal epileptic activity simultaneously increases preceding a thermally-evoked seizure. Epileptic events occur intermixed with SPW-R, some during SPW-R burst complexes, and transiently suppress SPW-R occurrence suggesting shared network elements. Together these data demonstrate a temperature dependence of SPW-R rate and ripple frequency and suggest a pathophysiologic mechanism by which elevated temperature transforms a normal brain rhythm into epileptic event.

Impairment of Sharp-Wave Ripples in a Murine Model of Dravet Syndrome.

Dravet syndrome (DS) is a severe early-onset epilepsy associated with heterozygous loss-of-function mutations in SCN1A Animal models of DS with global Scn1a haploinsufficiency recapitulate the DS phenotype, including seizures, premature death, and impaired spatial memory performance. Spatial memory requires hippocampal sharp-wave ripples (SPW-Rs), which consist of high-frequency field potential oscillations (ripples, 100-260 Hz) superimposed on a slower SPW. Published in vitro electrophysiologic recordings in DS mice demonstrate reduced firing of GABAergic inhibitory neurons, which are essential for the formation of SPW-R complexes. Here, in vivo electrophysiologic recordings of hippocampal local field potential in both male and female mice demonstrate that Scn1a haploinsufficiency slows intrinsic ripple frequency and reduces the rate of SPW-R occurrence. In DS mice, peak ripple-band power is shifted to lower frequencies, average intertrough intervals of individually detected ripples are slower, and the rate of SPW-R generation is reduced, while SPW amplitude remains unaffected. These alterations in SPW-R properties, in combination with published reductions in interneuron function in DS, suggest a direct link between reduced inhibitory neuron excitability and impaired SPW-R function. A simple interconnected, conductance-based in silico interneuron network model was used to determine whether reduced sodium conductance is sufficient to slow ripple frequency, and stimulation with a modeled SPW demonstrates that reduced sodium conductance alone is sufficient to slow oscillatory frequencies. These findings forge a potential mechanistic link between impaired SPW-R generation and Scn1a mutation in DS mice, expanding the set of disorders in which SPW-R dysfunction contributes to impaired memory.SIGNIFICANCE STATEMENT Disruption of sharp-wave ripples, a characteristic hippocampal rhythm coordinated by the precise timing of GABAergic interneurons, impairs spatial learning and memory. Prior in vitro patch-clamp recordings in brain slices from genetic mouse models of Dravet syndrome (DS) reveal reduced sodium current and excitability in GABAergic interneurons but not excitatory cells, suggesting a causal role for impaired interneuron activity in seizures and cognitive impairment. Here, heterozygous Scn1a mutation in DS mice reduces hippocampal sharp-wave ripple occurrence and slows internal ripple frequency in vivo and a simple in silico model demonstrates reduction in interneuron function alone is sufficient to slow model oscillations. Together, these findings provide a plausible pathophysiologic mechanism for Scn1a gene mutation to impair spatial memory.

Sleep impairment and reduced interneuron excitability in a mouse model of Dravet Syndrome.

Dravet Syndrome (DS) is caused by heterozygous loss-of-function mutations in voltage-gated sodium channel NaV1.1. Our mouse genetic model of DS recapitulates its severe seizures and premature death. Sleep disturbance is common in DS, but its mechanism is unknown. Electroencephalographic studies revealed abnormal sleep in DS mice, including reduced delta wave power, reduced sleep spindles, increased brief wakes, and numerous interictal spikes in Non-Rapid-Eye-Movement sleep. Theta power was reduced in Rapid-Eye-Movement sleep. Mice with NaV1.1 deleted specifically in forebrain interneurons exhibited similar sleep pathology to DS mice, but without changes in circadian rhythm. Sleep architecture depends on oscillatory activity in the thalamocortical network generated by excitatory neurons in the ventrobasal nucleus (VBN) of the thalamus and inhibitory GABAergic neurons in the reticular nucleus of the thalamus (RNT). Whole-cell NaV current was reduced in GABAergic RNT neurons but not in VBN neurons. Rebound firing of action potentials following hyperpolarization, the signature firing pattern of RNT neurons during sleep, was also reduced. These results demonstrate imbalance of excitatory vs. inhibitory neurons in this circuit. As predicted from this functional impairment, we found substantial deficit in homeostatic rebound of slow wave activity following sleep deprivation. Although sleep disorders in epilepsies have been attributed to anti-epileptic drugs, our results show that sleep disorder in DS mice arises from loss of NaV1.1 channels in forebrain GABAergic interneurons without drug treatment. Impairment of NaV currents and excitability of GABAergic RNT neurons are correlated with impaired sleep quality and homeostasis in these mice.

ABHD6 blockade exerts antiepileptic activity in PTZ-induced seizures and in spontaneous seizures in R6/2 mice.

The serine hydrolase α/ß-hydrolase domain 6 (ABHD6) hydrolyzes the most abundant endocannabinoid (eCB) in the brain, 2-arachidonoylglycerol (2-AG), and controls its availability at cannabinoid receptors. We show that ABHD6 inhibition decreases pentylenetetrazole (PTZ)-induced generalized tonic-clonic and myoclonic seizure incidence and severity. This effect is retained in Cnr1(-/-) or Cnr2(-/-) mice, but blocked by addition of a subconvulsive dose of picrotoxin, suggesting the involvement of GABAA receptors. ABHD6 inhibition also blocked spontaneous seizures in R6/2 mice, a genetic model of juvenile Huntington's disease known to exhibit dysregulated eCB signaling. ABHD6 blockade retained its antiepileptic activity over chronic dosing and was not associated with psychomotor or cognitive effects. While the etiology of seizures in R6/2 mice remains unsolved, involvement of the hippocampus is suggested by interictal epileptic discharges, increased expression of vGLUT1 but not vGAT, and reduced Neuropeptide Y (NPY) expression. We conclude that ABHD6 inhibition may represent a novel antiepileptic strategy.

Is there a clustering effect on electroencephalographic seizure localization?

Long-term video-EEG monitoring (LTM) is the gold standard for initial lateralization and localization of seizures in the workup for neurosurgical treatment of medically intractable epilepsy. Previous studies have yielded contradictory results as to whether seizures that occur in clusters tend to arise from the same brain region and may lead to the incorrect conclusion that seizures arise from a single focus. To determine whether seizure clustering affects localization in an LTM setting, the authors performed an observational study over 6 years at a large regional epilepsy center on those undergoing LTM for seizure diagnosis, characterization, or presurgical workup. Excluding repeat studies and LTMs with generalized or nonepileptic seizures resulted in 479 monitorings with 2774 focal seizures for analysis. Sequential pairs of consecutive focal seizures were classed as "concordant", "discordant," or "other," based on EEG localization. ANOVA analysis on the logarithm of the interseizure interval (LISI) among the three seizure pair groups showed no significant difference, p=0.47, nor did analysis defining concordance as lateralization to the same hemisphere (p=0.34). Analyses on subgroups with multifocal seizures, bilateral seizures, and extratemporal seizures all failed to show a significant difference. In conclusion, seizures have the same localizing value whether occurring in a cluster over a few hours or sporadically over a few days. This could potentially lead to shorter monitoring times.

Correlations in timing of sodium channel expression, epilepsy, and sudden death in Dravet syndrome.

Dravet Syndrome (DS) is an intractable genetic epilepsy caused by loss-of-function mutations in SCN1A, the gene encoding brain sodium channel Nav 1.1. DS is associated with increased frequency of sudden unexpected death in humans and in a mouse genetic model of this disease. Here we correlate the time course of declining expression of the murine embryonic sodium channel Nav 1.3 and the rise in expression of the adult sodium channel Nav 1.1 with susceptibility to epileptic seizures and increased incidence of sudden death in DS mice. Parallel studies with unaffected human brain tissue demonstrate similar decline in Nav 1.3 and increase in Nav 1.1 with age. In light of these results, we introduce the hypothesis that the natural loss Nav 1.3 channel expression in brain development, coupled with the failure of increase in functional Nav 1.1 channels in DS, defines a tipping point that leads to disinhibition of neural circuits, intractable seizures, co-morbidities, and premature death in this disease.

Sudden unexpected death in a mouse model of Dravet syndrome.

Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in intractable epilepsies, but physiological mechanisms that lead to SUDEP are unknown. Dravet syndrome (DS) is an infantile-onset intractable epilepsy caused by heterozygous loss-of-function mutations in the SCN1A gene, which encodes brain type-I voltage-gated sodium channel NaV1.1. We studied the mechanism of premature death in Scn1a heterozygous KO mice and conditional brain- and cardiac-specific KOs. Video monitoring demonstrated that SUDEP occurred immediately following generalized tonic-clonic seizures. A history of multiple seizures was a strong risk factor for SUDEP. Combined video-electroencephalography-electrocardiography revealed suppressed interictal resting heart-rate variability and episodes of ictal bradycardia associated with the tonic phases of generalized tonic-clonic seizures. Prolonged atropine-sensitive ictal bradycardia preceded SUDEP. Similar studies in conditional KO mice demonstrated that brain, but not cardiac, KO of Scn1a produced cardiac and SUDEP phenotypes similar to those found in DS mice. Atropine or N-methyl scopolamine treatment reduced the incidence of ictal bradycardia and SUDEP in DS mice. These findings suggest that SUDEP is caused by apparent parasympathetic hyperactivity immediately following tonic-clonic seizures in DS mice, which leads to lethal bradycardia and electrical dysfunction of the ventricle. These results have important implications for prevention of SUDEP in DS patients.

Synergistic GABA-enhancing therapy against seizures in a mouse model of Dravet syndrome.

Seizures remain uncontrolled in 30% of patients with epilepsy, even with concurrent use of multiple drugs, and uncontrolled seizures result in increased morbidity and mortality. An extreme example is Dravet syndrome (DS), an infantile-onset severe epilepsy caused by heterozygous loss of function mutations in SCN1A, the gene encoding the brain type-I voltage-gated sodium channel NaV1.1. Studies in Scn1a heterozygous knockout mice demonstrate reduced excitability of GABAergic interneurons, suggesting that enhancement of GABA signaling may improve seizure control and comorbidities. We studied the efficacy of two GABA-enhancing drugs, clonazepam and tiagabine, alone and in combination, against thermally evoked myoclonic and generalized tonic-clonic seizures. Clonazepam, a positive allosteric modulator of GABA-A receptors, protected against myoclonic and generalized tonic-clonic seizures. Tiagabine, a presynaptic GABA reuptake inhibitor, was protective against generalized tonic-clonic seizures but only minimally protective against myoclonic seizures and enhanced myoclonic seizure susceptibility at high doses. Combined therapy with clonazepam and tiagabine was synergistic against generalized tonic-clonic seizures but was additive against myoclonic seizures. Toxicity determined by rotorod testing was additive for combination therapy. The synergistic actions of clonazepam and tiagabine gave enhanced seizure protection and reduced toxicity, suggesting that combination therapy may be well tolerated and effective for seizures in DS.

Specific deletion of NaV1.1 sodium channels in inhibitory interneurons causes seizures and premature death in a mouse model of Dravet syndrome.

Heterozygous loss-of-function mutations in the brain sodium channel Na(V)1.1 cause Dravet syndrome (DS), a pharmacoresistant infantile-onset epilepsy syndrome with comorbidities of cognitive impairment and premature death. Previous studies using a mouse model of DS revealed reduced sodium currents and impaired excitability in GABAergic interneurons in the hippocampus, leading to the hypothesis that impaired excitability of GABAergic inhibitory neurons is the cause of epilepsy and premature death in DS. However, other classes of GABAergic interneurons are less impaired, so the direct cause of hyperexcitability, epilepsy, and premature death has remained unresolved. We generated a floxed Scn1a mouse line and used the Cre-Lox method driven by an enhancer from the Dlx1,2 locus for conditional deletion of Scn1a in forebrain GABAergic neurons. Immunocytochemical studies demonstrated selective loss of Na(V)1.1 channels in GABAergic interneurons in cerebral cortex and hippocampus. Mice with this deletion died prematurely following generalized tonic-clonic seizures, and they were equally susceptible to thermal induction of seizures as mice with global deletion of Scn1a. Evidently, loss of Na(V)1.1 channels in forebrain GABAergic neurons is both necessary and sufficient to cause epilepsy and premature death in DS.

Insights into pathophysiology and therapy from a mouse model of Dravet syndrome.

Mutations in voltage-gated sodium channels are associated with epilepsy syndromes with a wide range of severity. Complete loss of function in the Na(v) 1.1 channel encoded by the SCN1A gene is associated with severe myoclonic epilepsy in infancy (SMEI), a devastating infantile-onset epilepsy with ataxia, cognitive dysfunction, and febrile and afebrile seizures resistant to current medications. Genetic mouse models of SMEI have been created that strikingly recapitulate the SMEI phenotype including age and temperature dependence of seizures and ataxia. Loss-of-function in Na(v) 1.1 channels results in severely impaired sodium current and action potential firing in hippocampal γ-aminobutyric acid (GABA)ergic interneurons without detectable changes in excitatory pyramidal neurons. The resulting imbalance between excitation and inhibition likely contributes to hyperexcitability and seizures. Reduced sodium current and action potential firing in cerebellar Purkinje neurons likely contributes to comorbid ataxia. A mechanistic understanding of hyperexcitability, seizures, and comorbidities such as ataxia has led to novel strategies for treatment.

NaV1.1 channels and epilepsy.

Voltage-gated sodium channels initiate action potentials in brain neurons, and sodium channel blockers are used in therapy of epilepsy. Mutations in sodium channels are responsible for genetic epilepsy syndromes with a wide range of severity, and the NaV1.1 channel encoded by the SCN1A gene is the most frequent target of mutations. Complete loss-of-function mutations in NaV1.1 cause severe myoclonic epilepsy of infancy (SMEI or Dravet's Syndrome), which includes severe, intractable epilepsy and comorbidities of ataxia and cognitive impairment. Mice with loss-of-function mutations in NaV1.1 channels have severely impaired sodium currents and action potential firing in hippocampal GABAergic inhibitory neurons without detectable effect on the excitatory pyramidal neurons, which would cause hyperexcitability and contribute to seizures in SMEI. Similarly, the sodium currents and action potential firing are also impaired in the GABAergic Purkinje neurons of the cerebellum, which is likely to contribute to ataxia. The imbalance between excitatory and inhibitory transmission in these mice can be partially corrected by compensatory loss-of-function mutations of NaV1.6 channels, and thermally induced seizures in these mice can be prevented by drug combinations that enhance GABAergic neurotransmission. Generalized epilepsy with febrile seizures plus (GEFS+) is caused by missense mutations in NaV1.1 channels, which have variable biophysical effects on sodium channels expressed in non-neuronal cells, but may primarily cause loss of function when expressed in mice. Familial febrile seizures is caused by mild loss-of-function mutations in NaV1.1 channels; mutations in these channels are implicated in febrile seizures associated with vaccination; and impaired alternative splicing of the mRNA encoding these channels may also predispose some children to febrile seizures. We propose a unified loss-of-function hypothesis for the spectrum of epilepsy syndromes caused by genetic changes in NaV1.1 channels, in which mild impairment predisposes to febrile seizures, intermediate impairment leads to GEFS+ epilepsy, and severe or complete loss of function leads to the intractable seizures and comorbidities of SMEI.

Temperature- and age-dependent seizures in a mouse model of severe myoclonic epilepsy in infancy.

Heterozygous loss-of-function mutations in the alpha subunit of the type I voltage-gated sodium channel Na(V)1.1 cause severe myoclonic epilepsy in infancy (SMEI), an infantile-onset epileptic encephalopathy characterized by normal development followed by treatment-refractory febrile and afebrile seizures and psychomotor decline. Mice with SMEI (mSMEI), created by heterozygous deletion of Na(V)1.1 channels, develop seizures and ataxia. Here we investigated the temperature and age dependence of seizures and interictal epileptiform spike-and-wave activity in mSMEI. Combined video-EEG monitoring demonstrated that mSMEI had seizures induced by elevated body core temperature but wild-type mice were unaffected. In the 3 age groups tested, no postnatal day (P)17-18 mSMEI had temperature-induced seizures, but nearly all P20-22 and P30-46 mSMEI had myoclonic seizures followed by generalized seizures caused by elevated core body temperature. Spontaneous seizures were only observed in mice older than P32, suggesting that mSMEI become susceptible to temperature-induced seizures before spontaneous seizures. Interictal spike activity was seen at normal body temperature in most P30-46 mSMEI but not in P20-22 or P17-18 mSMEI, indicating that interictal epileptic activity correlates with seizure susceptibility. Most P20-22 mSMEI had interictal spike activity with elevated body temperature. Our results define a critical developmental transition for susceptibility to seizures in SMEI, demonstrate that body temperature elevation alone is sufficient to induce seizures, and reveal a close correspondence between human and mouse SMEI in the striking temperature and age dependence of seizure frequency and severity and in the temperature dependence and frequency of interictal epileptiform spike activity.

Successful long-term outcomes of spinal cord stimulation despite limited pain relief during temporary trialing.

Objectives. In spinal cord stimulation (SCS) therapy, limited pain relief during the temporary trial period is generally considered to be predictive of poor long-term benefit. To validate or refute this perception, the long-term outcomes of subjects who reported less than 50% pain relief during a temporary SCS trial were examined. Materials and Methods. Twelve subjects with intractable pain underwent implantation of trial SCS systems. After a trial period in which they reported less than 50% pain relief, they each received a permanent SCS implant. Pain ratings and complications were tracked for 6-18 months. Results. At the end of the temporary trial period, the average pain relief was 21%; no subject reported 50% or better pain relief. More favorable outcomes were reported after activation of the permanent system, however. At all follow-up time points, at least a third of the subjects reported better than 50% pain relief, and the average pain relief varied over time between 44% and 83%. All complications were readily resolved and no subjects withdrew from the study. Conclusions. Although SCS provided limited pain relief during the trial period, efficacy was more satisfactory after permanent implantation. Several subjects went on to experience nearly complete pain relief for up to 18 months (the maximum follow-up visit for study purposes), and no subject chose to discontinue SCS therapy. SCS appears to be a viable treatment option for patients who fail trials, raising some doubt as to the predictive sensitivity and specificity of the trial period. Thus, although outcome of a temporary trial period may be suggestive of later efficacy with SCS, it may not be the sole predictor of success. Alternatively, the arbitrary benchmark of 50% pain relief that is typically used to define the success of a temporary trial may be too stringent and unreliable.

Spinal cord stimulation has comparable efficacy in common pain etiologies.

Objectives. The probability of success with spinal cord stimulation (SCS) depends largely on appropriate patient selection. Here, we have assessed the predictive value of pain etiology as it relates to pain relief with SCS as part of a prospective multicenter clinical trial. Methods. Sixty-five subjects with chronic and intractable pain tested an epidural SCS system. Subjects reported pain ratings (visual analog scale) with stimulation off and stimulation on at scheduled follow-up visits for up to 18 months after activation of the system. Visual analog scale scores were averaged and stratified by dominant pain etiologies, comprising failed back surgery syndrome, complex regional pain syndrome, and a subgroup of subjects with miscellaneous other pain etiologies. Results. More than 70% of subjects in each subgroup had successful outcomes during the temporary trial period and similar percentages of subjects from each etiology subgroup subsequently went on to permanent implantation. After permanent implantation, all subgroups reported more than 50% pain relief, on average, at each follow-up time point. No predictive value of pain etiology was observed. Conclusions. Spinal cord stimulation is an effective therapy for neuropathic pain arising from a variety of causes. Failed back surgery syndrome, complex regional pain syndrome, and pain of other etiologies responded equally well to SCS.

A new spinal cord stimulation system effectively relieves chronic, intractable pain: a multicenter prospective clinical study.

Objectives. A prospective, open label, multicenter clinical trial confirmed the functionality of a new spinal cord stimulation (SCS) system for the treatment of chronic, intractable pain of the trunk and/or limbs. Materials and Methods. Sixty-five subjects tested a rechargeable 16-channel SCS system with individual current control of each contact on one or two percutaneous eight-contact epidural leads. After baseline measurements, subjects were tracked on pain ratings and complication rates for up to 18 months. Results. After a trial period, 75% of subjects underwent permanent implantation of the entire SCS system. More than one-half the implanted subjects experienced 50% or greater relief of pain after permanent implantation; some subjects reported relief of 90% or more of their pain. The most common complications after permanent implantation were lead migration, uncomfortable stimulation, and component failure; most resolved after reprogramming or device replacement. Conclusions. The new SCS system provided good pain relief to a majority of subjects, and the results confirm a favorable safety and efficacy profile for the SCS system.

Prevention of mechanical failures in implanted spinal cord stimulation systems.

Introduction. Spinal cord stimulation (SCS) is an effective procedure for the treatment of neuropathic extremity pain, with success rates approaching 70%. However, mechanical failures, including breakage and migration, can significantly limit the long-term effectiveness of SCS. A systematic analysis of surgical techniques was undertaken by a consensus group, coupled with extensive in vivo and in vitro biomechanical testing of system components. Methods. A computer model based on morphometric data was used to predict movement in a standard SCS system between an anchored lead and pulse generator placed in various locations. These displacements were then used to determine a realistic range of forces exerted on components of the SCS system. Laboratory fixtures were constructed to subject leads and anchors to repetitive stresses until failure occurred. An in vivo sheep model also was used to determine system compliances and failure thresholds in a biologically realistic setting. A panel of experienced implanters then interpreted the results and related them to clinical observations. Results. Use of a soft silastic anchor pushed through the fascia to provide a larger bend radius for the lead was associated with a time to failure 65 times longer than an anchored but unsupported lead. In addition, failures of surgical paddle leads occurred when used with an anchor, whereas without an anchor, no failures occurred to 1 million cycles. Based on these findings, the panel recommended a paramedian approach, abdominal pulse generator placement, maximizing bend radius by pushing the anchor through the fascia, and anchoring of the extension connector near the lead anchor. Discussion. Several factors are important in longevity of SCS systems. We discovered that technical factors can make a large difference in SCS reliability and that strict attention to these "best practices" will provide the best chance for maintaining the integrity of SCS systems over the long term.

Transverse tripolar spinal cord stimulation: results of an international multicenter study.

Experienced neurosurgeons at eight spinal cord stimulation centers in the United States, Canada, and Europe participated in a study from 1997 to 2000 investigating the safety, performance, and efficacy of a Transverse Tripolar Stimulation (TTS) system invented at the University of Twente, the Netherlands. This device was proposed to improve the ability of spinal cord stimulation to adequately overlap paresthesia to perceived areas of pain. Fifty-six patients with chronic, intractable neuropathic pain of the trunk and/or limbs more than three months' duration (average 105 months) were enrolled with follow-up periods at 4, 12, 26, and 52 weeks. All patients had a new paddle-type lead implanted with four electrodes, three of them aligned in a row perpendicular to the cord. Fifteen of these patients did not undergo permanent implantation. Of the 41 patients internalized, 20 patients chose conventional programming using an implanted pulse generator to drive four electrodes, while 21 patients chose a tripole stimulation system, which used radiofrequency power and signal transmission and an implanted dual-channel receiver to drive three electrodes using simultaneous pulses of independently variable amplitude. On average, the visual analog scale scores dropped more for patients with TTS systems (32%) than for conventional polarity systems (16%). Conventional polarity systems were using higher frequencies on average, while usage range was similar. Most impressive was the well-controlled "steering" of the paresthesias according to the dermatomal topography of the dorsal columns when using the TTS-balanced pulse driver. The most common complication was lead migration. While the transverse stimulation system produced acceptable outcomes for overall pain relief, an analysis of individual pain patterns suggests that it behaves like spinal cord stimulation in general with the best control of extremity neuropathic pain. This transverse tripole lead and driving system introduced the concept of electrical field steering by selective recruitment of axonal nerve fiber tracts in the dorsal columns.

Spinal cord stimulation: patient selection, technique, and outcomes.

Spinal cord stimulation, as with neuromodulation procedures in general, is a nondestructive, screenable, and reversible treatment option. Because there are no long-term side effects that have been reported; spinal cord stimulation is generally preferable as a first step when other less invasive treatments have failed to produce acceptable control of the pain.

Spinal cord stimulation: mechanisms of action.

STUDY DESIGN: A literature review and synthesis were performed. OBJECTIVE: To present the current understanding of the mechanisms of spinal cord stimulation in relation to the physiology of pain. SUMMARY OF BACKGROUND DATA: Spinal cord stimulation has been used for more than 30 years in the armamentarium of the interventional pain specialist to treat a variety of pain syndromes. Traditionally used for persisting leg pain after lumbar spinal surgery, it has been applied successfully in the treatment of angina pectoris, ischemic pain in the extremity, complex regional pain syndrome Types 1 and 2, and a variety of other pain states. This review presents the current status of what is known concerning how electrical stimulation of the spinal cord may achieve pain relief. METHODS: A literature review was conducted. RESULTS: The literature supports the theory that the mechanism of spinal cord stimulation cannot be completely explained by one model. It is likely that multiple mechanisms operate sequentially or simultaneously. CONCLUSION: Some clinical or experimental support can be found in the literature for 10 specific mechanisms or proposed mechanisms of spinal cord stimulation.

Enhanced transmission of glutamate current flowing from the dendrite to the soma in rat neocortical layer 5 neurons.

The presence of tetrodotoxin (TTX)-sensitive slowly-inactivating Na+ channels in the dendrites of neocortical layer 5 neurons was tested by focal iontophoresis of glutamate on the dendrite while voltage clamping the soma and proximal dendrite. The glutamate-transmitted current was measured with the voltage clamp circuit. When the soma was depolarized the transmitted current increased indicating voltage-dependent properties in the dendrite. Over 50% of this increased voltage-dependence was blocked by TTX indicating a large portion of the enhanced dendro-somatic current was caused non-inactivating Na+ channel inward rectification. The glutamate-transmitted current measured with a voltage clamp of the soma at firing level was equal to the effective glutamate measured during repetitive firing.