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Biomedical subjects

W F Agnew

Publications and source records attributed to W F Agnew.

At least 19 recordsLinked to original sources
PubMed1992

Damage in peripheral nerve from continuous electrical stimulation: comparison of two stimulus waveforms.

The propensity for two types of charge-balanced stimulus waveforms to induce injury during eight hours of continuous electrical stimulation of the cat sciatic nerve was investigated. One waveform was a biphasic, controlled-current pulse pair, each phase 50 microseconds in duration, with no delay between the phases ('short pulse', selected to excite primarily large axons), whereas in the second type each phase was 100 microseconds in duration, with a 400 microsecond delay between the phases (selected to excite axons of a broader spectrum of diameters). The sciatic nerve was examined for early axonal degeneration (EAD) seven days after the session of continuous stimulation. With both waveforms, the threshold stimulus current for axonal injury was greater than the current required to excite all of the nerve's large axons. The correlation between simple stimulus parameters and the amount of EAD was poor, especially with the 'short pulse' waveform, probably due to variability between animals. When the stimulus was normalised with respect to the current required to fully recruit the large axons, a good association between damage and stimulus amplitude emerged. The damage threshold was higher for the 'short pulse' waveform. The implications for clinical protocols are discussed.

Animals↗
PubMed1992

Stimulation with chronically implanted microelectrodes in the cochlear nucleus of the cat: histologic and physiologic effects.

The effects of several hours of continuous electrical stimulation in the cats' cochlear nucleus with chronically implanted activated iridium microelectrodes was investigated from the changes in the evoked response near the inferior colliculus and also by histologic evaluation of the stimulated tissue. The stimulating microelectrodes had geometric surface areas of 75-500 microns2. They were pulsed continuously for 4 h, at a pulse repetition rate of 200 Hz, using charge-balanced pulse pairs. The charge per phase was 1.8 or 3.6 nC/ph. The animals were sacrificed for histologic evaluation 2 h, or several days later. The only remarkable histologic change resulting from the 4 h of stimulation was some aggregation of lymphocytes at the site of stimulation. However, depression of the electrical excitability of neurons near the sites often persisted for several days after 4 h of stimulation at 3.6 nC/phase. The charge per phase of the stimulus pulse pair was correlated strongly with the depression of excitability, and there was a weaker correlation between the depression and the amplitude of the first phase of voltage transient induced across the electrode-tissue interface. The charge density, calculated from the geometric surface area of the stimulating electrodes, was poorly correlated with the severity of the depression. The findings suggest a means of detecting impending stimulation-induced neural damage while it is still reversible.

Animals↗
PubMed1990

Local anaesthetic block protects against electrically-induced damage in peripheral nerve.

This study is one of a series addressing the mechanisms involved in the production of neural damage caused by continuous, prolonged electrical stimulation of peripheral nerve. It has been previously shown that sustained, high frequency electrical stimulation of the cat's peroneal nerve may cause irreversible neural damage in the form of axonal degeneration of the large myelinated fibres. In this study we demonstrate that blocking the action potentials on most of the nerve fibres with local anaesthetics (10% procaine or 2% lidocaine) almost completely prevents the axonal degeneration. The abolition of axonal injury by local anaesthetic block strongly suggests that the electrically-induced damage is due to prolonged electrical excitation of axons. Furthermore, since less than complete suppression of the induced neural activity by local anaesthetic engenders essentially complete sparing of all axons, our results suggest that the damage to individual axons derives, at least in part, from stimulation-induced global changes in the nerve.

Action Potentials↗
PubMed1990

Partial pressure of oxygen in brain and peripheral nerve during damaging electrical stimulation.

The studies were performed to elucidate the mechanism underlying the neural damage which may occur during prolonged electrical stimulation of either brain tissue or peripheral nerve. The partial pressure of oxygen (pO2) was measured in the sciatic nerve and the cerebral cortex of adult cats before and during direct, local electrical stimulation of these neural tissues, using stimulus parameters capable of inducing neural injury. pO2 was monitored by the polarographic method, employing a platinum microelectrode inserted into the tissue adjacent to or beneath the stimulating electrode. In the sciatic nerve there was no marked change in intrafascicular pO2 in three cats upon initiation of the electrical stimulation. In a fourth animal intraneural pO2 increased briefly upon initiation of the stimulation. In no case did the intrafascicular compartment of nerves become significantly hypoxic. In the cerebral cortex, the start of stimulation was accompanied by a significant increase (approximately 12-15 Torr) in intracortical pO2 beneath the stimulating electrode, and pO2 remained at or above the pre-stimulus value for the duration of the stimulation. These results show that extracellular hypoxia is unlikely to be a significant factor in the neural injury induced in brain or peripheral nerve by prolonged electrical stimulation.

Animals↗
PubMed1990

Charge density and charge per phase as cofactors in neural injury induced by electrical stimulation.

The possibility of neural injury during prolonged electrical stimulation of the brain imposes some constraints on the use of this technique for therapeutic and experimental applications. Stimulating electrodes of various sizes were used to investigate the interactions of two stimulus parameters, charge density and charge per phase, in determining the threshold of neural injury induced by electrical stimulation. Platinum electrodes ranging in size from 0.002 to 0.5 cm2 were implanted over the parietal cortex of adult cats. Penetrating microelectrodes fabricated from iridium, with surface areas of 65 +/- 3 x 10(-6) cm2 were inserted into the parietal cortex. Ten days after implantation, the electrodes were pulsed continuously for 7h using charge balanced, current regulated, symmetric pulse pairs, 400 microseconds per phase in duration, at a repetition rate of 50 Hz. The animals were perfused immediately after the stimulation for histologic evaluation of the brain tissue subjacent to the electrode sites. The results show that charge density (as measured at the surface of the stimulating electrode), and charge per phase, interact in a synergistic manner to determine the threshold of stimulation-induced neural injury. This interaction occurs over a wide range of both parameters; for charge density from at least 10 to 800 microC/cm2 and, for charge per phase, from at least 0.05 to 5.0 microC per phase. The significance of these findings in elucidating the mechanisms underlying stimulation-induced injury is discussed.

Animals↗
PubMed1990

Considerations for safety with chronically implanted nerve electrodes.

Electrical stimulation of cranial and peripheral nerves has been used to ameliorate a variety of neurologic disease states and neural injuries over the past 20 years. In this review, clinical applications and the histopathologic results of chronic implants in animals and humans are discussed, and the results of neural damage models developed at Huntington Medical Research Institutes are summarized. Chronically implanted electrode arrays may produce neural injury by either mechanical factors or by continuous, high-frequency electrical stimulation. The margin of safety to avoid electrically induced injury may be increased by minimizing the frequency or total stimulation time, and by the use of an intermittent duty cycle. The protocols presently being used for the stimulation of the vagus nerve to effect inhibition of seizures appear to have an adequate margin of safety.

Animals↗
PubMed1989

Histologic and physiologic evaluation of electrically stimulated peripheral nerve: considerations for the selection of parameters.

Helical electrodes were implanted around the left and right common peroneal nerves of cats. Three weeks after implantation one nerve was stimulated for 4-16 hours using charge-balanced, biphasic, constant current pulses. Compound action potentials (CAP) evoked by the stimulus were recorded from over the cauda equina before, during and after the stimulation. Light and electron microscopy evaluations were conducted at various times following the stimulation. The mere presence of the electrode invariably resulted in thickened epineurium and in some cases increased peripheral endoneurial connective tissue beneath the electrodes. Physiologic changes during stimulation included elevation of the electrical threshold of the large axons in the nerve. This was reversed within one week after stimulation at a frequency of 20 Hz, but often was not reversed following stimulation at 50-100 Hz. Continuous stimulation at 50 Hz for 8-16 hours at 400 microA or more resulted in neural damage characterized by endoneurial edema beginning within 48 hours after stimulation, and early axonal degeneration (EAD) of the large myelinated fibers, beginning by 1 week after stimulation. Neural damage due to electrical stimulation was decreased or abolished by reduction of the duration of stimulation, by stimulating at 20 Hz (vs. 50 Hz) or by use of an intermittent duty cycle. These results demonstrate that axons in peripheral nerves can be irreversely damaged by 8-16 hours of continuous stimulation at 50 Hz. However, the extent to which these axons may subsequently regenerate is uncertain. Therefore, protocols for functional electrical stimulation in human patients probably should be evaluated individually in animal studies.

Animals↗
PubMed1988

Comparison of neural damage induced by electrical stimulation with faradaic and capacitor electrodes.

Arrays of platinum (faradaic) and anodized, sintered tantalum pentoxide (capacitor) electrodes were implanted bilaterally in the subdural space of the parietal cortex of the cat. Two weeks after implantation both types of electrodes were pulsed for seven hours with identical waveforms consisting of controlled-current, charge-balanced, symmetric, anodic-first pulse pairs, 400 microseconds/phase and a charge density of 80-100 microC/cm2 (microcoulombs per square cm) at 50 pps (pulses per second). One group of animals was sacrificed immediately following stimulation and a second smaller group one week after stimulation. Tissues beneath both types of pulsed electrodes were damaged, but the difference in damage for the two electrode types was not statistically significant. Tissue beneath unpulsed electrodes was normal. At the ultrastructural level, in animals killed immediately after stimulation, shrunken and hyperchromic neurons were intermixed with neurons showing early intracellular edema. Glial cells appeared essentially normal. In animals killed one week after stimulation most of the damaged neurons had recovered, but the presence of shrunken, vacuolated and degenerating neurons showed that some of the cells were damaged irreversibly. It is concluded that most of the neural damage from stimulations of the brain surface at the level used in this study derives from processes associated with passage of the stimulus current through tissue, such as neuronal hyperactivity rather than electrochemical reactions associated with current injection across the electrode-tissue interface, since such reactions occur only with the faradaic electrodes.

Animals↗
PubMed1987

Tissue response to potential neuroprosthetic materials implanted subdurally.

A histologic study was made of the response of the leptomeninges and underlying cerebral cortex of the cat to subdural implantation of 3 insulating materials (HR605-P, Parylene-C and PI-2555) and a polymeric electrode component (MMA/MAPTAC) for periods of 8 and 16 wk. The tissue reactions were compared with those elicited by the arrays of Dacron mesh matrices, pure platinum controls and by positive controls (Ag-AgCl) known to cause reactions in the brain. Sites beneath the Dacron mesh matrix, pure platinum control implants and beneath all insulating materials implanted for 8 and 16 wk appeared indistinguishable, exhibiting little tissue reaction. All neurons appeared normal. The leptomeninges and cortex beneath the Ag-AgCl implants showed a chronic inflammatory reaction after 8 and 16 wk. Despite varying amounts of oedema, gliosis and ingrowth of connective tissue in the molecular layer, virtually all underlying neurons appeared normal.

Animals↗
PubMed1987

Characterization of electrode dissolution products on the high-voltage electron microscope.

Deposits left by electrodes and biocompatibility test specimens implanted in brain or peripheral nerve were characterized by X-ray microprobe analysis, electron diffraction and stereoscopic imaging using a high-voltage electron microscope. Examination of thick (1-micron) sections of neural tissue confirmed that the electron-dense bodies found adjacent to electrode positions consist of elements originating in the implant material (with the exceptions of the S and Se found in association with Ag). These elements have no long-range order, suggesting they are complexed with biological molecules. In some cases the deposits appear to be caused by pulsing the electrode with current, while in other cases the deposits are corroded or abraded from the electrode or are otherwise not associated with the neuroprosthetic functioning of the implant.

Animals↗
PubMed1987

Considerations for safety in the use of extracranial stimulation for motor evoked potentials.

The possibility of neural damage during extracranial brain stimulation for motor evoked potentials (MEPs) is discussed from the perspective of animal studies in which the stimulating electrodes were in direct contact with the brain. These data indicate that the charge per phase used in most of the extracranial MEP protocols is sufficient to induce neural damage if the stimulation is applied continuously for several hours. However, in most cases dispersion of the stimulus current in the extracranial tissue and skull is probably adequate to attenuate the stimulus charge density at the brain surface to a safe level (less than approximately 40 microC/cm2 X ph). However, the possibility exists that low resistance paths between the stimulating electrode and the brain may give rise to foci of high charge density. The possibility of such focusing may be less with magnetic field than with direct electrical field stimulation. We stress the need for additional animal studies designed to delineate a range of safe stimulus parameters for this particular technique.

Animals↗
PubMed1986

Neuronal activity evoked by chronically implanted intracortical microelectrodes.

The averaged evoked compound action potentials (AECAPs) were recorded from the ipsilateral pyramidal tract of awake, unrestrained cats before, during, and after continuous electrical stimulation of the cerebral cortex via chronically implanted activated iridium or platinum-30% iridium (Pt30%Ir) microelectrodes. After stimulating 24 h at 20 pulses per second (pps), using charge-balanced, 200-microseconds pulse pairs of 40 to 80 microA (400 to 800 microC/cm2, 8 to 16 nC/phase (ph), 2 to 4 A/cm2), there was a transient elevation of the threshold of the early (direct) and of the alte (transynaptic) components of the AECAP. After cessation of continuous stimulation at 80 microA, the threshold of the early component of the AECAP remained elevated for as long as 24 h and the late component as long as 4 days, indicating significant but reversible depression of the electrical excitability of cortical neurons close to the microelectrodes. In three cats stimulated 23 h/day for 1 week, the AECAP also recovered to their prestimulus threshold. In contrast, pulsing for 24 h at 320 microA (3200 microC/cm2, 64 nC/ph, 16 A/cm2) produced marked elevation of the threshold of the AECAPs which was not reversed by 7 to 12 days after termination of intracortical stimulation. The electrical excitability of neurons adjacent to (unpulsed) microelectrodes 2 mm from the pulsed electrode was not affected. The observations reported here, in conjunction with the histologic results reported in the companion paper, indicate that both the Pt30%Ir and the iridium microelectrodes can be operated safely at currents to at least 80 microA, charge/ph of 16 A/cm2, and a charge density of 800 microC/cm2 X ph. However, on the basis of the electrophysiologic criteria, both types appear to be unsafe when pulsed at 320 microA (64 nC/ph, 3200 microC/cm2 X ph, 16 A/cm2).

Action Potentials↗
PubMed1986

Histopathologic evaluation of prolonged intracortical electrical stimulation.

Chronic stimulating microelectrodes fabricated from platinum-30% iridium (Pt-30%Ir) or activated iridium were implanted in assemblies of three in the left sensorimotor cortex of the cat and pulsed continuously at currents of 10 to 320 microA (100 to 3200 microC/cm2 X ph, 2 to 64 nC/ph) for periods of 24 h or for 23 h/day for 7 days. The microelectrodes had beveled tips with uninsulated geometric surface areas of 20 X 10(-6) cm2. Neuronal activity evoked by the focal stimulation was monitored by recording compound action potentials from the ipsilateral pyramidal tract. By this criterion neuronal activation thresholds were 5 to 15 microA (50 to 150 microC/cm2 X ph, 1 to 3 nC/ph) for both types of electrodes. Histologic evaluations of tissue surrounding the electrode tips were carried out by either light or electron microscopy. No neural damage was induced by 24 or 161 h of pulsing using either type of electrode at currents of 10 to 80 microA. Neural damage attributable to electrical stimulation per se was observed in a few sites pulsed with 320 microA (3200 microC/cm2 X ph, 64 nC/ph, 16 A/cm2) with Pt-30%Ir but not activated iridium electrodes of the same size. Electrode dissolution appears to be best correlated with charge density and current density. Dissolution of the Pt-30%Ir microelectrode tip was observed by scanning electron microscopy at charge densities as low as 200 microC/cm2 X ph (1 A/cm2), whereas erosion of activated iridium microelectrodes occurred only at the highest charge and current densities (3200 microC/cm2 X ph, 16 A/cm2). Thus, the activated iridium electrode is superior to Pt-30%Ir for chronic stimulations, from the standpoint of electrode tip stability, because with the former, in contrast to the alloy, detectable erosion occurred only at an intensity well above that required for activation of nearby neurons.

Animals↗
PubMed1984

A serum-free culture system for studying solute exchanges in the choroid plexus.

Organ cultures of choroid plexus tissues from the lateral ventricle of juvenile rats have been maintained for periods up to 7 wk in a chemically defined, serum-free media. Of several media and various supplements evaluated, the best growth and survival was obtained with the Pasadena Foundation for Medical Research-4 media supplemented with three hormones: epidermal growth factor, insulin, and hydrocortisone. Autoradiographic studies demonstrated that the epithelial cells incorporated [3H]leucine and [3H]thymidine indicating active protein and DNA synthesis, respectively. The organ cultures were characterized by bulbous, vesicular outgrowths from the choroidal villi explants. The fluid-filled lumina of the vesicles reached diameters of 900 microns and were easily accessed by micropipettes. The walls of the vesicles were composed of single layers of epithelial cells in which the ultrastructural features in the in vivo tissue were well maintained. The in vivo polarity (apical end toward the media and basilar end of the cells toward the luminal cavity) was also maintained. This morphologically stable in vitro system seems to be a promising model for investigation of secretory mechanisms of choroidal tissue.

Animals↗
PubMed1984

Histopathological evaluation of dog sacral nerve after chronic electrical stimulation for micturition.

Histological evaluations of dog sacral nerves were carried out after stimulation for electromicturition with three types of circumneural electrodes. The use of two types of cuff arrays was associated with a marked buildup of connective tissue around the nerve and filling the lumen of the array. Nerves within the first type of cuff array (having diameters approximately that of the nerve they surrounded) were often extruded from the lumen of the cuff. In some cases, this was accompanied by moderate or marked loss of axons. It is not clear whether this phenomenon was the result of the growth of connective tissue within the cuff or tension on the electrical leads. The damage cannot be attributed to the electrical stimulation because nerves enclosed by nonpulsed electrodes showed similar damage. The second type of cuff array used in the study had an oversize lumen. There was often considerable growth of connective tissue within the cuffs, but minimal or no mechanical deformation of the included nerves and minimal loss of axons. Because of sealable lips, extrusion of the nerve from this electrode was impossible. The nerves and arrays both functioned well, and there was minimal, if any, mechanical distortion of the nerves and minimal neural damage. Nerves within a third type of array ("spinal" array) also showed no or minimal damage. The array was implanted easily, and the delicate, springlike nature of the matrix allowed close apposition to nerves of different diameters while avoiding constriction of the nerve.

Animals↗
PubMed1983

Changes in extracellular potassium and calcium concentration and neural activity during prolonged electrical stimulation of the cat cerebral cortex at defined charge densities.

In cats anesthetized with nitrous oxide and halothane, ion-selecting microelectrodes were used to monitor changes in the concentration of potassium [K+]0 and calcium [Ca2+]0 in the extracellular compartment of the cerebral cortex during as long as 4 h of continuous stimulation of the cortical surface. At stimulus charge densities shown to induce only minimal localized histologic changes [20 microC/cm2 . ph at 50 pulses per second (pps)], [K+]0 at a depth of about 750 micrometers underwent only a transient increase at the beginning of stimulation, followed by a rapid return to the prestimulus concentration. [Ca2+]0 was unaffected. At a higher charge density (100 microC/cm2 . ph at 20 pps) there was a rapid transient increase in [K+]0, followed by a more gradual return to a plateau about 1 mM above the prestimulus value. [Ca+]0 usually underwent an initial increase followed by a slow decrease to a plateau value above 0.5 mM. At a charge density of 100 microC/cm2 . ph and 50 pps (shown in histological studies to induce significant neural damage), [Ca2+]0 slowly decreased to near or below 0.5 mM in the middle layers of the cortex. After 30 to 40 min of stimulation, [K+]0 underwent episodic fluctuations about a plateau value 0.5 to 1 mM above the prestimulus concentration. Simultaneous recordings of the compound action potential in the ipsilateral pyramidal tract indicated that these fluctuations were due to local changes in the excitability of intracortical circuitry conditioned by the intense stimulation. The results have implications for the possible interrelation of the changes in extracellular ionic concentrations and the early stages of stimulation-induced neural damage.

Animals↗
PubMed1983

Morphologic changes after prolonged electrical stimulation of the cat's cortex at defined charge densities.

Experiments were conducted correlating neuronal activity, changes in ionic concentrations in the cerebral extracellular compartment, and neural damage during 4-h continuous electrical stimulations of the cat's sensorimotor cortex. Here we describe histological evaluations with the light and electron microscope of cortical tissue subjected to charge-balanced, biphasic, constant-current pulses delivered through subdurally implanted electrodes. Three combinations of charge density and pulse repetition rate were used. The results indicated a positive correlation of neural damage with both charge density and total charge. With electrical stimulation of low charge density [20 microC/cm2 . ph, 50 pulses per second (pps)] a transient increase in [K+]0 was observed with no histologically demonstrable neural damage. The most intense electrical stimulation studied (100 microC/cm2 . ph, 50 pps) resulted in a tonic increase and episodic fluctuations of [K+]0 and a marked decrease in [Ca2+]0 accompanied by moderate neural damage in the form of shrunken neurons, widespread extracellular edema, and swollen axons and dendrites.

Animals↗