Increase In Stimulation Threshold Research Articles

Computational modelling of nerve stimulation and recording with peripheral visceral neural interfaces

Objective. Neuromodulation of visceral nerves is being intensively studied for treating a wide range of conditions, but effective translation requires increasing the efficacy and predictability of neural interface performance. Here we use computational models of rat visceral nerve to predict how neuroanatomical variability could affect both electrical stimulation and recording with an experimental planar neural interface. Approach. We developed a hybrid computational pipeline, Visceral Nerve Ensemble Recording and Stimulation (ViNERS), to couple finite-element modelling of extracellular electrical fields with biophysical simulations of individual axons. Anatomical properties of fascicles and axons in rat pelvic and vagus nerves were measured or obtained from public datasets. To validate ViNERS, we simulated pelvic nerve stimulation and recording with an experimental four-electrode planar array. Main results. Axon diameters measured from pelvic nerve were used to model a population of myelinated and unmyelinated axons and simulate recordings of electrically evoked single-unit field potentials (SUFPs). Across visceral nerve fascicles of increasing size, our simulations predicted an increase in stimulation threshold and a decrease in SUFP amplitude. Simulated threshold changes were dominated by changes in perineurium thickness, which correlates with fascicle diameter. We also demonstrated that ViNERS could simulate recordings of electrically-evoked compound action potentials (ECAPs) that were qualitatively similar to pelvic nerve recording made with the array used for simulation. Significance. We introduce ViNERS as a new open-source computational tool for modelling large-scale stimulation and recording from visceral nerves. ViNERS predicts how neuroanatomical variation in rat pelvic nerve affects stimulation and recording with an experimental planar electrode array. We show ViNERS can simulate ECAPS that capture features of our recordings, but our results suggest the underlying NEURON models need to be further refined and specifically adapted to accurately simulate visceral nerve axons.

The Usefulness of Intraoperative Neurophysiological Monitoring in Cervical Spine Surgery

The usefulness of intraoperative neurophysiological monitoring (IONM), including somatosensory-evoked potential (SSEP) and transcranial electrical motor-evoked potentials (TcMEPs) in cervical spine surgery still needs to be evaluated. We retrospectively reviewed 200 cervical spine surgery patients from 2008 to 2009 to determine the role of IONM in cervical spine surgery. Total intravenous anesthesia was used for all patients. IONM alerts were defined as a 50% decrease in amplitude, a 10% increase in latency, or a unilateral change for SSEP and an increase in stimulation threshold of more than 100 V for TcMEP. Three patients had SSEP alerts that were related to arm malposition (2 patients) and hypotension (1 patient). Five patients had TcMEP alerts: 4 alerts were caused by hypotension and 1 by bone graft compression of the spinal cord. All alerts were resolved when causative reasons were corrected. There was no postoperative iatrogenic neurological injury. The sensitivities of SSEP and TcMEP alerts for detecting impending neurological injury were 37.5% and 62.5%, respectively. The sensitivity of both SSEP and TcMEP used in combination was 100%. No false-positive and false-negative alerts were identified in either SSEP or TcMEP (100% specificity). The total intravenous anesthesia technique optimizes the detection of SSEP and TcMEP and therefore improves the sensitivity and specificity of IONM. SSEP is sensitive in detecting alerts in possible malposition-induced ischemia or brachial plexus nerve injury. TcMEP specifically detects hypotension-induced spinal functional compromises. Combination use of TcMEP and SSEP enhances the early detection of impeding neurological damage during cervical spine surgery.

Retigabine-induced population primary afferent hyperpolarisation in vitro

Retigabine is a compound of potential interest in analgesia which acts as an M-channel opener to depress neuronal excitability. Here we study the effects of retigabine and its antagonist XE-991 on populations of primary afferents. Experiments were performed using a hemisected spinal cord preparation from rat pups maintained under in vitro conditions. Recording from dorsal roots were performed using tight fitting suction electrodes coupled to AC and DC amplifiers. The adjacent dorsal root was electrically stimulated at regular intervals. The effects of the modulators on basal potential, spontaneous potentials and dorsal root-dorsal root responses were studied. Superfusion of retigabine (10 μM) produced long lasting and robust hyperpolarisation of primary afferents which persisted during superfusion of picrotoxin (20 μM) and tetrodotoxin (0.5 μM). Other effects of retigabine were (1) increase in stimulation threshold; (2) increase in size of responses to suprathreshold stimuli; and (3) increase in amplitude and decrease in frequency of spontaneous dorsal root potentials. Superfusion of XE-991 had little effect on its own but blocked all the effects of retigabine. These results indicate the presence of functional M-currents in central terminals of primary afferents and in the interneurones that mediate dorsal root potentials. The depressant effects of retigabine on the excitability of these structures may contribute to its analgesic effects after pain-inducing treatments.

Long-term superiority of steroid elution in atrial active fixation platinum leads.

Steroid elution reduces the acute increase in stimulation threshold particularly in active fixation leads. The aim of this study was to investigate the long-term efficacy of steroid elution in atrial screw-in leads compared to conventional lead design. Two different bipolar active fixation platinum lead designs were implanted. Leads were similar except for the presence (group S, n = 66) or absence (group N, n = 68) of steroid elution. Patients received dual chamber pacemakers with the following atrial leads in consecutive order: Medtronic 4058 M (group N, n = 30), Medtronic 4068 (group S, n = 40), Vitatron IMS 13 (identical to 4058 M, group N, n = 38), and Vitatron IMX 13 (identical to 4068, group S, n = 26). The mean follow-up period was 40.7 +/- 16.1 months (range 10 to 84 months). Stimulation thresholds, pacing impedances, P wave potentials, and sensing threshold were assessed for both groups immediately, 10 days, 6 weeks, and 3 months after implantation followed by 6-months intervals. Energy thresholds, chronaxie-rheobase products, and energy consumption of atrial pacing were calculated. Chronic values were deduced from the most recent measurement performed in an individual patient. Within the first 10 days after implantation, atrial voltage threshold at pulse duration of 0.4 ms increased from 0.91 +/- 0.42 to 2.06 +/- 0.45 V in group N (P < 0.001). Less increase was observed in group S (0.83 +/- 0.39 to 1.08 +/- 0.53 V, P = 0.003). Atrial voltage thresholds remained markedly lower in steroid-eluting leads during whole follow-up (1.12 +/- 0.49 V in group S vs 1.58 +/- 0.71 V in group N, P < 0.001). Chronic energy consumption was markedly reduced in group S (4.0 +/- 2.7 microJ) compared to group N (9.8 +/- 7.5 microJ, P < 0.001). An atrial voltage threshold below 1.25 V at 0.4 ms was achieved in 92.3% of patients of group S allowing programming of an output of 2.5 V. Such low outputs were feasible in only 49.3% of patients in group N (P < 0.001). Chronic P wave amplitudes did not differ significantly between groups (3.27 +/- 1.81 mV in group N vs 3.24 +/- 1.18 mV in group S, P = 0.91). Steroid elution diminishes the increase of stimulation thresholds of nonsteroid atrial active fixation platinum leads resulting in a long-term reduction of energy consumption. Thus, use of steroids can be recommended for general use in atrial active fixation lead designs.

Acute and chronic performance of a steroid eluting electrode for ventricular pacing

Studies have demonstrated consistently low stimulation thresholds in the first months following implantation of steroid eluting electrodes. There have been no reported cases of exit block. There is little information on the long-term performance of these leads. Data were collected on 15 patients in whom Medtronic steroid eluting leads (5023 and 4003) had been implanted in 1987. Stimulation thresholds were measured at implantation and at weeks 1, 2, 3, 4, 5, 6 and 12. Stimulation threshold, lead impedance and sensing thresholds were monitored periodically for 3 yr using the telemetered function of the pulse generator. Three-month follow-up was obtained in all the patients and 3-yr follow-up in 10. Stimulation thresholds remained low throughout the follow-up period in all but one patient who developed exit block necessitating the replacement of the pacing system. In the remaining patients there was a significant increase in mean stimulation threshold from implantation to week 1 (mean stimulation threshold at implantation = 0.106 ms, mean ST at week 1 = 0.182 ms; p = 0.05), and also a gradual increase in the stimulation threshold over the first 2 yr of follow up (mean stimulation threshold 1 week = 0.182 ms, mean stimulation threshold months 13–24 = 0.243 ms; p = 0.05). Lead impedance showed no significant change over the follow-up period (mean change in impedance = 4.3 Ω, SD 163.2, p = 0.97). Unlike many conventional electrodes, steroid eluting leads show no early peak in stimulation threshold but exit block can occur. Stimulation thresholds show a small but significant rise over time.

Characterization of descending modulation of nociception from the A5 cell group

The present study examined the role of the A5 catecholamine-containing cell group in descending modulation of the nociceptive tail-flick (TF) reflex and regulation of blood pressure and heart rate in rats lightly anesthetized with petobarbital. Systematic mapping studies throughout the A5 cell group, rostral to caudal, showed that electrical stimulation in and near the A5 cell group at intensities as low as 25 μA was sufficient to inhibit the tail-flick (TF) reflex without producing a significant pressor response. Microinjections of glutamate into the same sites to selectively activate cell bodies also produced inhibition of the TF reflex and were accompanied by significant decreases in blood pressure(mean, −23 ± 4.7mmHg, n = 21) and non-significant decreases in heart rate(−7.6 ± 11bpm). Intrathecal administration of the receptor antagonists phentolamine, yohimbine, prazosin, methysergide, naloxone or atropine revealed that descending inhibition from the A5 cell group produced by electrical stimulation is mediated in part by spinal opioid and α-adrenoceptors. Increases in stimulation thresholds in the A5 cell group for inhibition of the TF reflex of 28.3 and 24.1% were produced by intrathecal pretreatment with phentolamine and naloxone, respectively. None of the other receptor antagonists produced significant increases in stimulation thresholds in the A5 cell group for inhibition of the TF reflex. Resting blood pressure and heart rate were not affected by the receptor antagonists.

Long-lasting Epidural Sensory Blockade by n-Butyl p-Aminobenzoate in the Dog

An aqueous suspension of n-butyl p-aminobenzoate (BAB), a highly lipid-soluble congener of benzocaine, was applied epidurally and around ulnar nerves in dogs. The suspension consisted of 10% BAB and 0.025% polysorbate in 0.9% NaCl. Sensory effects were tested by electrical stimulation. Three epidural injections were given, and the dogs were killed after 21 days. The increase in stimulation threshold was comparable to the effect of lidocaine in a concentration between 0.5% and 1%. Increased sensory threshold lasted for days, whereas no long-lasting motor effects were observed. Pathomorphologic changes were found primarily in the dorsal spinal nerve roots, although slight changes were also found in the ventral spinal roots. White matter degeneration was found only in the lumbar dorsal columns. This result suggested Wallerian degeneration in the dorsal spinal nerves and was at variance with recently published data on epidural BAB. No changes were observed in the ulnar nerves. The authors demonstrated that the pathomorphologic changes were induced by the BAB suspension and not by the suspending additive polysorbate 80. It was postulated that the suspension of BAB, which contains particles of a median size of 15 microns, was mainly confined to the dorsal epidural space where neurolytic changes in axons of the dorsal spinal nerve roots and dorsal columns are induced. This may explain the long-lasting sensory effects seen in intractable cancer pain patients after epidural BAB administration. More research is necessary to define the distribution of BAB in nervous tissue after its epidural administration and to better characterize toxicity, neurolytic effects, and regeneration of nervous tissue after BAB administrations.

Characterization of descending modulation of nociception from the A5 cell group

The present study examined the role of the A5 catecholamine-containing cell group in descending modulation of the nociceptive tail-flick (TF) reflex and regulation of blood pressure and heart rate in rats lightly anesthetized with petobarbital. Systematic mapping studies throughout the A5 cell group, rostral to caudal, showed that electrical stimulation in and near the A5 cell group at intensities as low as 25 μA was sufficient to inhibit the tail-flick (TF) reflex without producing a significant pressor response. Microinjections of glutamate into the same sites to selectively activate cell bodies also produced inhibition of the TF reflex and were accompanied by significant decreases in blood pressure(mean, −23 ± 4.7mmHg, n = 21) and non-significant decreases in heart rate(−7.6 ± 11bpm). Intrathecal administration of the receptor antagonists phentolamine, yohimbine, prazosin, methysergide, naloxone or atropine revealed that descending inhibition from the A5 cell group produced by electrical stimulation is mediated in part by spinal opioid and α-adrenoceptors. Increases in stimulation thresholds in the A5 cell group for inhibition of the TF reflex of 28.3 and 24.1% were produced by intrathecal pretreatment with phentolamine and naloxone, respectively. None of the other receptor antagonists produced significant increases in stimulation thresholds in the A5 cell group for inhibition of the TF reflex. Resting blood pressure and heart rate were not affected by the receptor antagonists.

Brain-stem relays mediating stimulation-produced antinociception from the lateral hypothalamus in the rat

Several lines of evidence have demonstrated a role for the lateral hypothalamus (LH) in an endogenous system of descending inhibition. The present study, in rats lightly anesthetized with pentobarbital, was undertaken to examine systematically the organization in the brain stem of pathways mediating descending inhibition of the nociceptive tail flick (TF) reflex produced by focal electrical stimulation in the LH. The microinjection of lidocaine into the midbrain, dorsolateral pons, or medial medulla resulted in significant increases in stimulation thresholds in the LH for inhibition of the TF reflex (89.1, 67.4, and 73.6%, respectively). Selective lesions of cell bodies in the midbrain or medulla by the neurotoxin ibotenic acid also produced significant increases in stimulation thresholds in the LH for inhibition of the TF reflex (31.6 and 131.6%, respectively), thus revealing relays in the periaqueductal gray and the nucleus raphe magnus located between the LH and the lumbar spinal cord. The failure of ibotenic acid to affect LH-produced descending inhibition when microinjected into the dorsolateral pons, and the significant effect produced by lidocaine microinjected into the same area, implicates fibers of passage in the dorsolateral pons in descending inhibition of the TF reflex produced by focal electrical stimulation in the LH. The fluorescent dye Fast blue and HRP conjugated to wheat germ agglutinin were used to confirm that the area stimulated in the LH has reciprocal connections with the periaqueductal gray and nucleus raphe magnus.

Serotonin and/or an excitatory amino acid in the medial medulla mediates stimulation-produced antinociception from the lateral hypothalamus in the rat

Several lines of evidence have demonstrated a role for the lateral hypothalamus (LH) in an endogenous system of descending inhibition. Descending inhibition from the LH relies, at least in part, on a relay(s) in the midbrain and/or medulla. The medullary nucleus raphe magnus (NRM) serves as one such relay. The present study, in rats lightly anesthetized with pentobarbital, was undertaken to systematically examine the transmitter(s) in the medial medulla mediating descending inhibition of the nociceptive tail flick (TF) reflex produced by focal electrical stimulation in the LH. The microinjection of pharmacologic receptor antagonists (5 μg) into the NRM revealed that the glutamate receptor antagonists, γ- d-glutamylglycine and 2-amino-5-phosphonovalerate produced the largest increases in stimulation thresholds in the LH for inhibition of the TF reflex (107.6% and 102.6%, respectively). Methysergide, a serotonin receptor antagonist, also produced a significant increase (81.5%) in the stimulation threshold in the LH for inhibition of the TF reflex. The opioid receptor antagonist, naloxone, however, was without effect, producing only a 4.0% increase in the LH stimulation threshold. These results suggest that serotonin and/or an excitatory amino acid are transmitters at the bulbar relay in the medial medulla mediating descending inhibition of the TF reflex produced by focal electrical stimulation in the LH.

The influence of ischaemia on the electrophysiological properties of amiodarone in chronically treated rabbit hearts.

The effects of 30 min zero-flow ischaemia and reperfusion on the electrophysiological properties of amiodarone were studied in 11 rabbits treated with oral amiodarone (mean 117 mg kg-1, day-1) for 2-3 months, and 11 controls. Experiments were performed in vitro in the isolated perfused interventricular septum, and preischaemic values were compared with those obtained in right ventricular papillary muscles from the same hearts. Prior to ischaemia, mean values of action potential duration (APD90) and effective refractory period (ERP) were prolonged by 13% in the amiodarone-treated septa. Action potential upstroke velocity (Vmax) was reduced by 14% in the septa, but by 42% in papillary muscles. Ischaemia resulted in shortening of APD90 in both control and amiodarone-treated septa, with a loss of the ability of amiodarone to prolong APD90. In contrast, ischaemia resulted in a greater fall in Vmax, gross lengthening in conduction time and increase in stimulation threshold in the amiodarone-treated septa compared with controls. Reperfusion resulted in a restoration of the action of amiodarone on repolarization, and resolution of the marked effects on excitability and conduction. The electrophysiological properties of amiodarone are considerably altered in ischaemic myocardium, with a reversible loss of its ability to prolong repolarization, but evidence suggestive of a marked enhancement of its effect on the inward sodium current.

Spinal monoamine mediation of stimulation-produced antinociception from the lateral hypothalamus

Stimulation-produced antinociception can be evoked from a wide variety of sites in the brain, including the lateral hypothalamus (LH). The present study, in rats lightly anesthetized with pentobarbital, examined descending inhibition of the nociceptive tail flick (TF) reflex produced by focal electrical stimulation in the LH and the neurotransmitter(s), at the level of the lumbar enlargement, mediating the inhibition. Systematic tracking studies demonstrated that stimulation in the diencephalon dorsal to the hypothalamus did not reliably inhibit the TF reflex. Inhibition of the TF reflex was produced, however, throughout the hypothalamus at intensities of stimulation typically between 50 and 200 μA. The area requiring low intensities of stimulation (50–100 μA) to inhibit the TF reflex was a diffuse region of the LH, inferior to the mammillothalamic tract and internal capsule, medial to the supraoptic decussation and including the medial forebrain bundle. Microinjections of S-glutamate (100 mM, 0.5μl) in the LH did not inhibit the TF reflex, suggesting that activation of fibers of passage by stimulation was responsible for inhibition of the TF reflex produced from the LH. The intrathecal administration of pharmacologic antagonists (15–30 μg; naloxone, methysergide, phentolamine, prazosin or yohimbine) revealed that the α-adrenoceptor antagonists phentolamine and yohimbine produced the greatest increases in stimulation thresholds in the LH for inhibition of the TF reflex (83.7% and 89.8%, respectively). The intrathecal administration of methysergide produced a lesser, but statistically significant 11% increase in the stimulation threshold for inhibition of the TF reflex. These results indicate that spinal α 2-adrenoceptors primarily mediate the descending inhibition of the TF reflex produced by electrical stimulation in the LH.

Characterization of coeruleospinal inhibition of the nociceptive tail-flick reflex in the rat: Mediation by spinal α 2-adrenoceptors

Several lines of evidence implicate bulbospinal noradrenergic pathways in antinociception and descending inhibition. In the present study, descending inhibition of the nociceptive tail-flick (TF) reflex by electrical stimulation in the dorsolateral pons (DLP) and the spinal neurotransmitter(s) mediating that inhibition were characterized in lightly pentobarbital-anesthetized rats. It was determined that 10 s of stimulation in the DLP prior to the application of heat to the tail resulted in optimum (lowest) thresholds for inhibition of the TF reflex. Conditioning-test studies indicated that the duration of the inhibitory effects produced by stimulation outlasted the 10-s period of stimulation by approximately 5 s. Systematic mapping studies revealed that inhibition of the TF reflex could be produced by stimulation throughout a large portion of the DLP; however, stimulation sites requiring the lowest intensities of stimulation (less than or equal to 25 microA) were in the locus coeruleus/subcoeruleus. Changes in blood pressure were not produced at this intensity and duration of stimulation. S-glutamate microinjections and stimulation strength-duration determinations suggest that inhibition of the TF reflex produced by stimulation in the locus coeruleus/subcoeruleus results from activation of cell bodies. The intrathecal administration of pharmacologic antagonists (phentolamine, yohimbine, prazosin, naloxone, methysergide, atropine and bicuculline) revealed that only the alpha-adrenergic antagonists phentolamine and yohimbine resulted in significant increases in stimulation thresholds in the locus coeruleus/subcoeruleus for inhibition of the TF reflex (83.1 and 93.9%, respectively). These results indicate that inhibition of the spinal nociceptive TF reflex produced by electrical stimulation in the locus coeruleus/subcoeruleus is at least in part a noradrenergic, postsynaptic alpha 2-adrenoceptor-mediated effect.

The porous-surfaced electrode: A new concept in pacemaker lead design

Three major problems which may be encountered with endocardial pacemaker electrodes are a lack of stable position, a chronic increase in stimulation threshold, and a diminishing magnitude of the sensed endocardial signal. These problems are particularly manifest in the atrium. Having previously shown that porous metal surfaces can support stable tissue ingrowth in both bloodstream and soft tissue environments, we set out todetermine the performance of porous-surfaced endocardial pacing electrodes in the atrial position. In two groups of six dogs each, J-shaped atrial leads with Elgiloy electrode tips (2.3 mm. in diameter, 2.3 mm. in length), having either conventional smooth surfaces (control) or porous surfaces (20 to 50 micron particle size) produced by powder metallurgy techniques, were positioned in the right atrial a-pendage. Stimulation thresholds and P-wave amplitude were repeatedly measured until the dogs were put to death 30 w-eks following implantation. The presence or absence of electrode fixation was observed and the atrial tissue reaction was examined grossly and by both light and scanning electron microscopy (SEM). The porous-surfaced electrodes demonstrated superior long-term stimulation thresholds which, at 30 weeks, averaged less then one third of those in the control group. In addition, the porous group showed a small but significant improvement in the amplitude of the sensed P wave. None of the smooth-surfaced electrodes showed fixation, and the tissue reaction consisted of a thick layer of granulation and fibrous tissue on the underlying endocardium, widely separating the electrode from the myocardium. In contrast, all of the porous-surfaced electrodes were fexed to the endocardium by fibrous tissue ingrowth into the surface pores. This tissue fixation of the electrode tip in close proximity to underlying myocytes explains their superior performance.

Low Threshold Endocardial Electrodes for Permanent Cardiac Pacing

Three different electrodes, i.e. conventional large and small surface endocardial electrodes and a new large contact area-small active surface electrode, have been compared with respect to their stimulation thresholds for cardiac pacing in 94 patients with 96 electrodes. Both capacitor discharge and constant current pulses were used for the measurements. The average 2 msec impulse threshold for the 47 mm(2) electrode reached its maximum on the 14th postoperative day and was 3.6+/-1.4 V and 4.4+/-1.8 mA. One month after insertion, the threshold was 3.2+/-1.4 V and 3.9+/-1.7 mA. Corresponding values after one month for the 6 mm(2) electrode were 2.0+/-1.0 V and 1.7+/-0.9 mA and for the new electrode 1.7+/-0.9 V and 1.4+/-0.8 mA. Thresholds increased by about 20% when the impulse duration was diminished from 2 to 0.5 msec. The new large area-small active surface electrode offers advantages of significantly smaller increases in stimulation thresholds during the first month after insertion and good attachment to the endocardium.

Changing hyperactivity response thresholds with substances influencing biogenic amines

The influence of a direct change in the biogenic amines of the central nervous system on the stimulation threshold of rats for a particular behavioural response, motor hyperactivity, was investigated. Norepinephrine, 5-hydroxytryptamine and dopamine were administered intrahypothalamically. An increase in stimulation threshold was clearly observed only after benzoquinolizine, injected intraperitoneally. Other substances caused little or no change in the stimulation threshold. There were no specific influences of norepinephrine, 5-hydroxytryptamine and dopamine on the stimulation threshold in these experiments.

Neurophysiological analysis of antidepressants acting on responses of limbic system

1. After administration of antidepressants (banactyzine, chloracizine, imipramine, amitriptyline) dissociation of behavioral and EEG responses to electrical stimulation of limbic structures (amygdala, hippocampus, septum) is observed. 2. A neurophysiological feature distinguishing the action of antidepressants (imipramine, amitriptyline) is depression of function of the amygdala. This was shown by an increase in threshold for stimulation and a lowered intensity of behavioral responses, although EEG responses of paroxysmal type could be increased under these circumstances. 3. Neurophysiological analysis shows that the effect of antidepressants is complex and differential in character, i.e., although they inhibit the function of some limbic structures, they also either stimulate or do not affect the function of others.