Influence of pulse sequence, polarity and amplitude on magnetic stimulation of human and porcine peripheral nerve.

1. Mammalian phrenic nerve, in a trough filled with saline, was excited by magnetic coil (MC)-induced stimuli at defined stimulation sites, including the negative-going first spatial derivative of the induced electric field along a straight nerve, at a bend in the nerve, and at a cut nerve ending. At all such sites, the largest amplitude response for a given stimulator output setting was elicited by an induced damped polyphasic pulse consisting of an initial quarter-cycle hyperpolarization followed by a half-cycle depolarization compared with a predominantly 'monophasic' quarter-cycle depolarization. 2. Simulation studies demonstrated that the increased efficacy of the induced quarter-cycle hyperpolarizing-half-cycle depolarizing polyphasic pulse was mainly attributed to the greater duration of the outward membrane current phase, resulting in a greater outward charge transfer afforded by the half-cycle (i.e. quarter-cycles 2 and 3). The advantage of a fast rising initial quarter-cycle depolarization was more than offset by the slower rising, but longer duration depolarizing half-cycle. 3. Simulation further revealed that the quarter-cycle hyperpolarization-half-cycle depolarization showed only a 2.6 % lowering of peak outward current and a 3.5 % lowering of outward charge transfer at threshold, compared with a half-cycle depolarization alone. Presumably, this slight increase in efficacy reflects modest reversal of Na+ inactivation by the very brief initial hyperpolarization. 4. In vitro, at low bath temperature, the nerve response to an initial quarter-cycle depolarization declined in amplitude as the second hyperpolarizing phase progressively increased in amplitude and duration. This 'pull-down' phenomenon nearly disappeared as the bath temperature approached 37 C. Possibly, at the reduced temperature, delay in generation of the action potential permitted the hyperpolarization phase to reduce excitation. 5. Pull-down was not observed in the thenar muscle responses to median nerve stimulation in a normal human at normal temperature. However, pull-down emerged when the median nerve was cooled by placing ice over the forearm. 6. In a nerve at subnormal temperature straddled with non-conducting inhomogeneities, polyphasic pulses of either polarity elicited the largest responses. This was also seen when stimulating distal median nerve at normal temperature. These results imply excitation by hyperpolarizing-depolarizing pulse sequences at two separate sites. Similarly, polyphasic pulses elicited the largest responses from nerve roots and motor cortex. 7. The pull-down phenomenon has a possible clinical application in detecting pathologically slowed activation of Na+ channels. The current direction of the polyphasic waveform may become a significant factor with the increasing use of repetitive magnetic stimulators which, for technical reasons, induce a cosine-shaped half-cycle, preceded and followed by quarter-cycles of opposite polarity.

Preliminary evidence for the evolution in complexity of heart rate dynamics during autonomic maturation in neonatal swine.

Previous studies suggest that the autonomic nervous system plays an important role in the generation of complex heart rate dynamics. Therefore, we hypothesized that the complexity (irregularity) of cardiac interbeat intervals would evolve with the maturation of autonomic innervation to the heart. Twelve healthy newborn piglets were implanted with ECG transmitters and studied at one or more different ages up to 33 days of age, the period during which pigs develop functional sympathetic innervation of the heart from the stellate ganglia. Three animals underwent right stellate ganglionectomy, two a left stellate ganglionectomy, two a right cardiac vagotomy and five a sham procedure. The statistic, approximate entropy (ApEn), was used to quantify the regularity of interbeat interval fluctuations. Sham-operated animals showed an increase in the standard deviation (SD) and irregularity (ApEn) of cardiac interval fluctuations with increasing age. Right stellate ganglionectomized piglets had lower interbeat interval ApEn values, but similar SD's by 26-27 days of age compared to sham-operated animals. Left stellate ganglionectomy, which affects cardiac inotropy rather than chronotropy, had no effect on cardiac interval irregularity, while vagotomy had an indeterminant effect. The increasing irregularity of interbeat interval dynamics during autonomic maturation and the apparent attenuation of heartbeat irregularity when right stellate ganglion innervation is interrupted, provides empirical support for the notion that complex heartbeat dynamics in the mature animal are the result of a network of autonomic neural pathways that enables an organism to adapt to stress.

A new method using neuromagnetic stimulation to measure conduction time within the cauda equina.

Using principles derived from electric field measurements and studies of phrenic nerve in vitro, neuromagnetic stimuli in humans were predicted to excite selective low threshold sites in proximal and distal cauda equina. Physical models, in which induced electric fields were recorded in a segment of human lumbosacral spine immersed in a saline filled tank, supported this prediction. Conclusions from the model were tested and confirmed in normal human subjects. Ipsilateral motor evoked potentials were elicited in lower limb muscles and striated sphincters by magnetic coil (MC) stimulation of both proximal and distal cauda equina. Over proximal cauda equina a vertically oriented MC junction and cranially directed induced current elicited a newly identified compound muscle action potential (CMAP). The F response latency and lack of attenuation when the target muscle was vibrated suggest that the proximal response is a directly elicited M response arising near or at the rootlet exit zone of the conus medullaris. Over distal cauda equina, lumbar roots were optimally excited by a horizontally oriented MC junction, and sacral roots by an approximately vertically oriented MC junction, eliciting CMAPs with similar appearance but shorter latency consistent with the known intrathecal lengths of the lower lumbar and sacral nerve roots. The induced current was usually most effective when directed towards the spinal fluid filled thecal sac. Normal subjects showed stable CMAP onset latencies elicited at proximal and distal cauda equina despite wide variation in amplitude. Thus, cauda equina conduction time can be directly calculated. This new method may improve the detection and classification of peripheral neuropathies affecting lower limbs and striated sphincters.

In vitro evaluation of a 4-leaf coil design for magnetic stimulation of peripheral nerve.

The performance of a 4-leaf magnetic coil was evaluated during magnetic stimulation of a peripheral nerve in vitro. The site of stimulation was below the coil center, and a 90 degrees rotation of the coil was equivalent to a change in current polarity. A hyperpolarizing magnetic stimulus failed to slow or block a propagating action potential.

Recognition potential: sensitivity to visual field stimulated.

The recognition potential (RP) was distinguished from P3 and eye blink responses by its sensitivity to visual area stimulated. Images were flashed in upper and lower hemifields. Current source density profiles were computed, using 16 midline scalp electrodes. For P3 and eye blink profiles, the hemifield stimulated was not a significant factor. For the recognition potential, upper and lower field stimulation produced radically different profiles. An improved recognition potential signal was obtained by a new mathematical procedure. It used the difference in sensitivity to visual area stimulated to reject P3 and eye blink responses.

Magnetic coil stimulation of straight and bent amphibian and mammalian peripheral nerve in vitro: locus of excitation.

1. According to classical cable theory, a magnetic coil (MC) should excite a linear nerve fibre in a homogeneous medium at the negative-going first spatial derivative of the induced electric field. This prediction was tested by MC stimulation of mammalian phrenic and amphibian sciatic nerve and branches in vitro, immersed in Ringer solution within a trough, and identifying the sites of excitation by recording responses of similar latency to local electrical stimulation. Subsequently, the identified sites of excitation were compared with measurements of the induced electric field and its calculated first spatial derivative. A special hardware device was used to selectively reverse MC current direction and to generate predominantly monophasic- or polyphasic-induced pulse profiles whose initial phases were identical in polarity, shape and amplitude. When using the amphibian nerve preparation, a complication was excitation at low threshold points related to cut branches. 2. Reversal of monophasic current resulted in latency shifts corresponding approximately to the distance between induced cathode and anode. The location of each site of excitation was at, or very near, the negative-going first spatial derivative peaks of the induced electric field measured parallel to the straight nerve. Significantly, excitation of the nerve did not occur at the peak of the induced electric field above the centre of the 'figure of eight' MC junction. 3. A polyphasic pulse excited the nerve at both sites, by the negative-going first phase at one location, and approximately 150 microseconds later, by the reversed negative-going second phase at the other location. Polyphasic and monophasic pulses elicited responses with similar latency when the induced current flowed towards the recording electrode. 4. Straddling a nerve with non-coding solid lucite cylinders created a localized spatial narrowing and increase in the induced electric field, resulting in a lowered threshold of excitation. The corresponding closer spacing between first spatial derivative peaks was exhibited by a significant reduction in latency shift when MC current direction was reversed. 5. When a nerve is bent and the induced current is directed along the nerve towards the bend, the threshold of excitation is reduced there. Increasing the angle of the bend from 0 deg to more than 90 deg graded the decrease in threshold. 6. In a straight nerve the threshold was lowest when current was directed towards the cut end.(ABSTRACT TRUNCATED AT 400 WORDS)

Respiratory modulation of sympathetic activity in neonatal swine.

Spontaneous efferent sympathetic activity (cervical sympathetic and splanchnic nerves) was recorded simultaneously with efferent phrenic discharge, with aortic pressure, and with the electrocardiogram in less than 1- to 51-day-old neonatal swine anesthetized with Saffan (alfaxalone). Power spectral analyses of sympathetic discharge revealed a frequency range of 4-36 Hz, with peaks distributed in four regions of the spectrum (4-6 Hz, 8-15 Hz, 16-22 Hz, and 28-36 Hz). Inspiratory modulation was readily apparent since sympathetic power spectral energy was greatest during the time of phrenic activity. Alterations in pulmonary afferent inputs (e.g., lung inflation tests and/or vagotomy) altered both phrenic and sympathetic activity. Use of the respiratory-cardiac modulation ratio indicated that respiratory modulation of sympathetic activity was greater than cardiac modulation. Complex afferent inputs, i.e., fictive Valsalva maneuver, indicated an immaturity of integration within the cardiovascular regulatory system. The adult patterns of blood pressure changes and heart rate responses were delayed until approximately 1 mo of age. Calculations of Valsalva ratios (ratio of maximal R-R interval to minimal R-R interval) indicated delayed onset of heart rate responses, reflecting the maturation of cardiovascular reflexes during the neonatal period.

Power spectral analysis of the baroreflex in neonatal swine.

The baroreflex was observed in neonatal swine as young as 4 h of age. Bolus injections of Na nitroprusside (NP) and phenylephrine (PE), induced changes in blood pressure and elicited changes in both heart rate and in cervical sympathetic and splanchnic discharge; changes in sympathetic discharge were reflected in altered power spectral magnitude. Measures of heart rate showed that the magnitude of the PE-induced decreases was positively correlated with increasing postnatal age. The results indicate that the baroreflex, as indicated by changes in sympathetic discharge and heart rate, is present in early neonatal swine.

Measurement of the electric field induced into inhomogeneous volume conductors by magnetic coils: application to human spinal neurogeometry.

We measured the electric fields induced by round and figure "8" magnetic coils (MCs) in homogeneous and inhomogeneous volume conductors. In homogeneous media, the round MC held tangential (i.e., flat) to the volume conductor induced an annular electric field. When the round MC was held on-edge (i.e., orthogonal) to the volume conductor, the induced electric field consisted of two loops mainly parallel to the surface of the volume conductor and which approximated each other directly under the contacting edge of the MC. The tangentially oriented figure "8" MC similarly induced two electric field loops which approximated one another maximally under the region of the junction in its long axis. In a complex inhomogeneous volume conductor, such as a segment of human cervical-thoracic vertebral spine located eccentrically within a large cylindrical tank and submerged in isotonic saline, the direction of electric fields within the spinal canal and across the intervertebral neuroforamina was similar to that observed in the homogeneous volume conductor. However, in and near a single neuroforamen, the electric field and especially its first spatial derivative were markedly elevated compared to that recorded within the long central axis of the vertebral canal. Motor unit and compound muscle action potentials elicited in limb muscles by MC stimulation of human cervical spine confirmed predictions derived from the physical model. The predictions included: (1) absence of spinal cord stimulation compared to relative ease of nerve root stimulation by current that is most likely concentrated at the neuroforamina. When stimulating current is directed towards the periphery, the most likely low threshold site of stimulation is inferred to be just distal to the neuroforamina. It is emphasized that with supramaximal stimulation, more distal sites of excitation may occur; (2) invariant latency shifts at threshold intensities when moving the MC along the rostrocaudal axis of the cervical vertebral column; (3) significant effect (on motor unit activation thresholds) of the direction of induced current flow across the neuroforamina; (4) reduced stimulation when the targeted nerve roots are close to the null point of the electric field, i.e., between locations of high electric field intensity, of opposite polarity; and (5) relatively focal nerve root stimulation by the junction of a transversely orientated figure "8" MC, i.e., parallel to the nerve roots.

Magnetic coil stimulation of human visual cortex: studies of perception.

The effects of magnetic coil (MC) stimulation of human visual cortex on the foveal perception of briefly presented letter trigrams include: (1) letters were nearly always reported correctly at visual stimulus-MC pulse intervals less than 60-80 msec or greater than 120-140 msec. Thus, by 120-140 msec, information related to letter recognition is relayed from calcarine cortex. (2) Presentation of equiluminant chromatic stimuli (specifically green letters against a red background) results in suppression curves which commence at longer latencies than those obtained with achromatic stimuli. (3) At a stimulus-MC pulse interval of 100 msec, shifting the MC laterally or rostrally resulted in suppression of the contralateral or caudal-most letter respectively. This implies a focal, topographical effect on visual cortex. (4) Two trigram stimuli separated in time (e.g. 100 msec) resulted in classical backward masking in which S1 (the target) was suppressed by S2 (the mask), using an S2/S1 luminance-contrast ratio of 4:1. When the MC was subsequently discharged 80-100 msec after S2, and S2 was suppressed, the response to S1 was easily retrieved (unmasked). Presumably, by 160 msec, S1 has been transmitted to the next processing, extrastriate level. (5) The unmasking phenomenon has been used to track information flow from visual cortex to higher cortical centers (e.g. Wernicke's, Broca's, and related areas). (6) Using a prototype repetitive stimulator, a consecutive train of single MC pulses given 70, 143 and 216 msec following a brief alphabetic trigram stimulus elicited a significant reduction in letter perception. This notably contrasts with the absence of suppression when a single MC pulse was given 70 or 143 msec following presentation of the alphabetic trigram. The results with 3 pulses suggest that the first MC pulse (at 70 msec) delays but requires repetition to prevent processing and/or transmission of information from visual cortex.

Mechanisms of peripheral nervous system stimulation using the magnetic coil.

We measured the distribution of the electric fields induced within isotropic and anisotropic volume conductors by figure '8' and round magnetic coils (MCs). For various MC orientations maximal electric fields were induced parallel to the inner surface of the volume conductor. Predictions from physical models roughly approximating human forearm and vertebral column were then tested by MC stimulation of distal median nerve at the wrist and nerve roots at the cervical spine, respectively. Predictions that were confirmed included: (1) Peripheral nerve is most easily excited by a tangential-edge round MC in which current is induced parallel to the long axis of the nerve. As a corollary, peripheral nerve is least excited when the round MC is geometrically bisected by the long axis of the nerve. (2) Peripheral nerve excitation most likely occurs at locations corresponding to the first spatial derivative of the electric field; i.e. where the electrical field is changing most rapidly over distance. For the figure '8' MC, this occurs distally when the anterior divergence of the junction is directed distally. (3) Nerve roots are excited at a relatively constant latency, low threshold location. This site most likely corresponds to the vicinity of the neuroforamina where the induced electric field is most intense and the first spatial derivatives peak. By contrast, the low value of the first derivative in the longitudinal axis of the vertebral canal implies that long tracts in the spinal cord are not likely to be excited using commercially available MCs. Our study also indicates that intracranial stimulation of facial nerve occurs at a selected low threshold location, probably reflecting focusing of induced current.

Effects of anesthesia on efferent phrenic activity in neonatal swine.

The effects of two levels of Saffan anesthesia (standard recording level: 2-4 mg/kg/min, and 10X recording level) and a single level of pentobarbital (5 mg/kg) on the power spectral density of efferent phrenic discharge were investigated in piglets aged from less than 1 day to 50 days. The phrenic high frequency oscillation (HFO) was present in decerebrate, unanesthetized piglets and in piglets anesthetized with Saffan, albeit reduced at 10 times recording level, but was absent under pentobarbital. The results indicate that Saffan does not have a significantly depressant effect on the phrenic HFO in developing swine.

Age-related changes in power spectra of efferent phrenic activity in the piglet.

Power spectral analysis of phrenic nerve discharge in neonatal swine revealed the presence of both high-frequency oscillations (HFO) (95-150 Hz) and medium-frequency oscillations (MFO) (15-35 Hz). The HFO was shown to be age-related; the MFO was not. The data indicated that at least one manifestation of maturation of the respiratory rhythm generator is the increase with age of the frequency of the HFO.

Acoustic facilitation of the Hoffmann reflex.

The facilitative effect of a pure tone on the amplitude of the Hoffmann reflex was tested in 11 subjects under four conditions: (i) trying not to respond to the tone, (ii) voluntary abduction of the right index finger in response to the tone, (iii) voluntary plantarflexion of the left leg, and (iv) right plantarflexion in response to the tone. The acoustic stimulus was a 1000-Hz pure tone (80 dB, re 0.0002 dyne/cm2), presented on a random set of trials. Tone onset occurred 100 ms prior to the electrical stimulus that evoked the Hoffmann reflex. The Hoffmann reflex was larger for "tone" trials than for "silent" trials. The facilitative effect was equal in four cases: (i) making no response (NR), (ii) finger abduction (FA), (iii) noninvolved muscle (NIM), and (iv) involved muscle during treadle pressing (IM). The effect of the first tone presented was larger than that of subsequent tones, indicating some habituation of the acoustic effect on the H-reflex. Tests for spontaneous recovery and stimulus generalization were not significant. The results supported the existence of a purely auditory facilitation of spinal excitability.

Computer feedback reveals quantal aspects of the Hoffmann reflex.

The Hoffmann reflex was studied in 13 normal volunteers, using computer feedback to control stimulus intensity. The intensity of the electrical pulse that evoked the H-reflex was maintained at near threshold values by a computer program, which increased or decreased the intensity on the basis of the amplitude of the recorded response. Stimulus intensity was increased for H-responses less than, and decreased for H-responses greater than, a criterion value of 50 microV peak-to-peak. More than 500 responses were recorded from each subject during a 40-min period. The feedback procedure tended to hold the H-reflexes near the criterion value. Slow drifts in the required current indicated waxing and waning of threshold. Examination of response amplitude distributions showed two different types. For the nonquantal type, all possible values were represented in the range zero to 200 microV. Responses in the upper half of that range were less frequent than those in the lower half. For the quantal type, the majority of the responses were clustered near zero and at an amplitude that was characteristic for a given recording configuration; very few responses of intermediate amplitude were observed. The quantal pattern of response was ascribed to the firing of low-threshold single motor units.