Excitation of visual cortex neurons by local intracortical microstimulation

The threshold current required for the excitation of visual cortex neurons in the vicinity (approximately 1 mm) of an intracortical stimulating electrode was measured as a function of the stimulus pulse duration in the anesthetized cat. For cortical neurons with latencies of activation from 0.4 to 3.4 ms and for stimulus pulse durations from 0.02 to 0.7 ms, the threshold current for all neurons tested decreased in an exponential fashion as the pulse width was increased. Rheobase current values (ampere-threshold) were 1.2 to 516 muA (mean 160 +/- 24 muA, N = 24) and chronaxie values were 0.07 to 0.79 ms (mean 0.217 +/- 0.036 ms, N = 24). When the quantity of charge required for neuronal excitation was calculated, a quasilinear relationship was found between threshold charge and stimulus pulse width. The minimum threshold charge (coulomb-threshold) occurred for the briefest pulse widths tested and were 2 to 86 nC (mean 36.4 +/- 4.4 nC, N = 24). When the pulse energy index was calculated (threshold current squared multiplied by the pulse width), the minimum pulse energy capable of generating an evoked response (a single action potential) occurred when the pulse width was approximately 80% greater than the chronaxie. These studies demonstrate that the predictions derived from A. V. Hill's classical theory of nerve excitation are to a first approximation obeyed by visual cortex neurons. For the three parameters analyzed as a function of stimulus pulse width, the pulse current is minimized at long pulse durations, the pulse charge is minimized at short pulse durations, and the pulse energy is minimized at pulse widths of intermediate value.     

Relevance of stimulus duration for activation of motor and sensory fibers: implications for the study of H-reflexes and magnetic stimulation.

Electric stimuli with durations of 0.5-1.0 msec are optimal for studies of H-reflexes. It is more difficult to obtain H-reflexes with shorter duration stimuli or with magnetic stimulation. In order to understand this behavior, we studied the excitation thresholds for motor and sensory fibers in the ulnar, median and tibial nerves using both electric and magnetic stimulation. For short duration electrical stimuli (0.1 msec) the threshold for motor fibers is lower than for sensory fibers. For longer duration electric stimuli (1.0 msec) the threshold for sensory fibers is lower. For magnetic stimulation the threshold for motor fibers is much lower than for sensory fibers. Thus, stimulus duration is a critical parameter for sensory fiber excitation, and current magnetic stimulators are not optimal.     

Tooth pulp-evoked activity in the spinal trigeminal nucleus caudalis of cat: comparison to primary afferent fiber, reflex, and sensory responses

Tooth pulp-evoked single-neuron responses were recorded in the spinal trigeminal nucleus caudalis of the cat. The thresholds to monopolar electric pulses of various durations (0.2 to 20 ms) were determined using a constant current stimulator. With stimulus pulse durations of 10 to 20 ms, the thresholds were comparable with those of primary afferent A-fibers, although the most sensitive primary afferent fibers had lower thresholds. Primary afferent C-fibers had higher thresholds than the postsynaptic neurons studied. The threshold for the tooth pulp-elicited jaw-opening response was obtained at a lower stimulus intensity than the liminal response in most postsynaptic neurons of this study. The threshold rise of the postsynaptic trigeminal neurons with decreasing stimulus pulse duration (from 5 to 0.2 ms) was much steeper than that of primary afferent A-fibers or jaw-opening response. The strength-duration curves for tooth pulp-elicited pain sensations in man resemble those of spinal trigeminal neurons. Sixty-two percent of the units had a threshold elevation during a noxious pinch of the tail. The results indicate that the activation of postsynaptic trigeminal neurons requires a considerable temporal summation of primary afferent impulses. The jaw reflex thresholds cannot be explained by the properties of the neurons in the subnucleus caudalis of the trigeminal tract. The results support the concept that dental pain is based on the activation of spinal trigeminal nucleus caudalis neurons receiving their input from intradental A-fibers.     

Effect of ECT stimulus parameters on seizure physiology and outcome

This study examined the effect of low- and high-pulse frequency stimulus electroconvulsive therapy on seizure physiology and therapeutic outcome. Forty depressed patients randomly received either low (n = 19) or high (n = 21) pulse frequency stimulus during a course of right unilateral electroconvulsive therapy. The current and pulse width were kept constant whereas the duration was proportionately varied. The two groups were compared for seizure parameters and therapeutic outcome. Low frequency stimulus group had lower threshold and less subconvulsive stimulation. There were no differences in seizure durations, ictal cardiovascular responses and therapeutic outcome between the two groups. Low frequency stimulus produced seizure at lower stimulus dose without affecting seizure parameters and therapeutic effects.     

Threshold suprachoroidal-transretinal stimulation current resulting in retinal damage in rabbits

The purpose of this study is to determine the threshold suprachoroidal-transretinal stimulation (STS) current that results in retinal damage in rabbits. Biphasic STS pulses (anodic first, frequency 20 Hz) were used to stimulate the retina of pigmented rabbits (n = 18) continuously for 1 h using a 100 microm diameter platinum wire electrode. The STS current that induced retinal damage after 1 h was determined by ophthalmoscopy or by fluorescein angiography (FA) independently. The effect of the pulse duration on the threshold current was investigated. Histological studies were performed after electrical stimulation experiments. The threshold for a safe current to the retina was 0.6 mA for a duration of 0.5 ms. The threshold for a safe charge increased approximately linearly with an increase of stimulus duration but the threshold for a safe current decreased logarithmically with an increase of duration. The threshold for a safe electrical energy remained almost constant for all durations. Histological examination showed severe retinal damage when the current exceeded the threshold, with more damage in the inner layers compared with the outer layers of the retina. The threshold for the safe current was higher than that reported for direct stimulation of neural tissues, suggesting that the STS method was safe and able to be used with a retinal prosthesis. Because the threshold for the safe charge was lower with shorter pulse durations, care should be taken using pulses of short durations.     

Depolarization amplitude and Ca2+-inflow control the time course of quantal releases at murine motor nerve terminals

In order to test whether the time courses of quantal releases after a depolarization pulse are affected by the depolarization amplitude, time courses were measured for small depolarization pulses that elicited close to threshold releases and for large depolarizations that elicited releases approaching saturation level. Diaphragms of young mice were excised and superfused with Bretag's solution at 18°C. Synaptic currents were elicited and recorded through a perfused macropatch pipette. Releases elicited by threshold depolarizations rose earlier than releases elicited by saturation depolarizations. The short delays in the rising phases of release after large depolarizations may be due to the shift of Ca²⁺ currents flowing during the pulse to tail currents. After its peak, release decayed with a time constant τ. For saturation depolarizations τ was about 0.3 ms, and for threshold depolarizations τ increased up to 0.8 ms. In order to differentiate between the effects of variations in Ca²⁺ inflow and in depolarization, the amplitudes of large depolarization pulses were held constant while the amount of release was depressed by halving the Ca²⁺ concentration at the terminal. The time course of the lowered releases was slightly delayed while τ remained at 0.3 ms as typical for saturation depolarizations. Double pulse facilitation unexpectedly revealed a short phase of depression of release after the pulse. This depression may contribute to the rapid decay (τ) of release after large depolarizations. The dependence of τ on depolarization amplitude indicates that the final phase of the time course of release is largely controlled by the amplitude of the preceding depolarization.     

Potassium translocation and spreading depression induced by electrical stimulation of the brain

Cathodal current pulses with durations from 20 ms to 80 s were applied to the surface of rat parietal neocortex, and the strength-duration properties of the threshold stimulus for initiation of spreading depression was determined. In one series, extradural stimulation was used. In a second series, a liquid electrode was used, the dura was opened, and K+-sensitive microelectrodes were used to determine the time course of extracellular K+ concentration during and after each stimulus pulse. With the dura open, the strength-duration curve was of the form It0.55 = constant. With extradural stimulation, the slope of the log-log plot relating current intensity to pulse duration changed gradually as the pulse duration increased, averaging 0.63. Theoretical analysis suggests that diffusion of K+ away from a zone of current-induced accumulation can account for these slope data. Applicability of this mechanism of K+ accumulation to observed changes in sensitivity of neurons to repeated stimulation at subcortical sites is considered.     

Perturbation of the direction of neurite growth by pulsed and focal electric fields

We have studied the orientation of neurite growth in the culture of embryonic Xenopus neurons in response to three types of extracellular electric fields: spatially uniform pulsed fields, focally applied steady (DC) fields, and focally applied pulsed fields. Under uniform pulsed fields, neurites showed a preferential orientation toward the cathode pole of the field in a manner similar to that previously found for DC fields. The extent of neurite orientation depended upon the duration, amplitude, and frequency of the pulse but appeared to be similar to that produced by a uniform DC field of an equivalent time-averaged field intensity. For square pulses of 5 msec duration, the minimal amplitude and frequency required to produce a detectable orientation of neurite growth over a period of 24 hr were 2.5 V/cm and 10 Hz, which correspond to a time-averaged field intensity of 125 mV/cm. Steady or pulsed focal fields were applied by passing a current through a micropipette placed near the growth cone of the neurite. Fields of negative polarity (current sink) were found to attract the growth cone, whereas fields of positive polarity (current source) were found to deflect the growth cone away from the pipette. The threshold DC current density needed at the growth cone to perturb its direction of growth within 15 min was 0.2 to 2 pA/micron2 (or 3 to 30 mV/cm); and for focal pulsed currents (pulse duration 5 msec), a typical combination of minimal pulse amplitude and frequency was 4 pA/micron2 and 10 Hz. This threshold focal current is similar to that which occurs at the synaptic cleft during active synaptic activity.     

Strength-duration properties of cathodal pulses eliciting spreading depression in rat cerebral cortex

Strength-duration curves for the threshold stimulus for initiation of spreading depression were determined for durations of 2 ms to 120 s, using cathodal surface stimulation through a well-defined area. With the dura open, the strength-duration curve was of the form I square root t = constant. With extradural stimulation, the slope of the log-log plot relating current intensity to pulse duration increased gradually as the pulse duration increased.     

Multichannel surface recordings on the visual cortex: implications for a neuroprosthesis

Using a multi-channel platinum surface electrode array, recordings from cat primary visual cortex were obtained in response to visual stimuli, and electrical stimuli delivered using the elements of the array itself. Neural responses to electrical stimuli were consistent, regardless of stimulus polarity or leading phase (biphasic), although thresholds were lower for monophasic than biphasic pulses. Both visual and electrical stimuli reliably evoked responses with characteristic components, which interacted with each other in a nonlinear summation showing first facilitation then suppression during the window of interaction. The chronaxie for eliciting threshold cortical responses was about 100 mus, and the charge density with a pulse width of 50-100 mus was around 55 muC cm(-2). These data form the basis of understanding the types of cortical responses to stimuli delivered by devices suitable for chronic implantation.     

Impact of pulse duration in single pulse TMS

Objective

The intensity of transcranial magnetic stimulation (TMS) is typically adjusted by changing the amplitude of the induced electrical field, while its duration is fixed. Here we examined the influence of two different pulse durations on several physiological parameters of primary motor cortex excitability obtained using single pulse TMS.

Methods

A Magstim Bistim² stimulator was used to produce TMS pulses of two distinct durations. For either pulse duration we measured, in healthy volunteers, resting and active motor thresholds, recruitment curves of motor evoked potentials in relaxed and contracting hand muscles as well as contralateral (cSP) and ipsilateral (iSP) cortical silent periods.

Results

Motor thresholds decreased by 20% using a 1.4 times longer TMS pulse compared to the standard pulse, while there was no significant effect on threshold adjusted measurements of cortical excitability. The longer pulse duration reduced pulse-to-pulse variability in cSP.

Conclusions

The strength of a TMS pulse can be adjusted both by amplitude or pulse duration. TMS pulse duration does not affect threshold-adjusted single pulse measures of motor cortex excitability.

Significance

Using longer TMS pulses might be an alternative in subjects with very high motor threshold. Pulse duration might not be relevant as long as TMS intensity is threshold-adapted. This is important when comparing studies performed with different stimulator types.     

The effect of pulse duration of refractory periods of neurons mediating brain-stimulation reward

The post-stimulation excitability characteristics of neurons mediating the rewarding effects of electrical stimulation of the medial forebrain bundle were behaviorally assessed at 5 different pulse durations. Recovery from refractoriness was inferred from the results of double-pulse tests in which the interval between conditioning (C) and test (T) pulses of equal amplitude was varied. Pulses of 0.1-0.5 ms had little effect on the time course of recovery which ranged from 0.4 to about 1.5 ms in each animal. In some subjects, however, complete recovery from refractoriness was significantly delayed with 1- and 2-ms pulses, with as much as a tripling in the C-T interval at which recovery approached asymptotic levels. This effect appeared to be placement-specific and was well correlated with the threshold charge, which ranged from 0.5 to 1.3 microC. The highest charge values were obtained in those subjects in which longer pulses displaced the refractory period profile towards a slower recovery; the electrode tips in this group were located in more anterior positions than those subjects in which pulse duration had no effect on recovery from refractoriness. It appears that at some placements slowly recovering elements can contribute to the circuitry underlying brain-stimulation reward when suitable stimulation parameters are employed.     

Effects of superimposed electrical stimulation on perceived discomfort and torque increment size and variability

Superimposed electrical stimulation techniques can be used to detect central activation failure (CAF), that is, incomplete central nervous system recruitment or suboptimal activation of motor units. The purpose of this study was to evaluate the effects of two stimulation parameters on perceived discomfort and torque increment size and variability. Discomfort was evaluated using a visual analog scale (0-100 mm) for pain. The rectus femoris muscle of the dominant leg of 24 young healthy men was stimulated during submaximal (80% maximal) voluntary contractions. The size and variability of torque increments and perceived discomfort were assessed following stimulation with: (1) pulse trains (100 HZ, 150 V, 0.2-ms pulse duration) of different lengths (50 ms and 100 ms); and (2) pulse trains (100 HZ, 100 ms, 150 V) with different pulse durations (0.2 ms and 0.1 ms). Pulse trains of 100 ms generated larger torque increments and produced less variability, but caused more discomfort than pulse trains of 50 ms. Average discomfort ratings for pulse trains of 100 ms were 43.1 mm, and of 50 ms were 53.2 mm. There was no difference in torque increment size or in variability between pulse trains with pulse durations of 0.1 ms and 0.2 ms, whereas discomfort was less for the shorter pulse durations; average discomfort ratings were 53.1 mm and 58.1 mm for pulse durations of 0.1 ms and 0.2 ms, respectively. Thus, the appropriate selection of stimulation parameters can reduce discomfort but maintain the ability to detect CAF.     

Parameters for direct cortical electrical stimulation in the human: histopathologic confirmation.

Safe parameters for electrical cortical stimulation in humans are difficult to estimate from the animal experimental literature. We therefore examined the light microscopic histology at a total of 11 sites of direct subdural electrical stimulation, taken as part of anterior temporal lobectomies in 3 patients. Stimulations had been done through 3.175 mm diameter electrodes, with 0.3 msec square wave pulses of alternating polarity at 50 pulses/sec. In 2 patients, one site each had been used as a common reference for stimulation, receiving over 251 stimulation trials, most of 2-5 sec duration, at currents of 12.5-15.0 mA, 1 day prior to resection. The maximum charge per phase was 4.0-4.4 microC; the maximum charge density was 52-57 microC per geometric cm2 per pulse at the electrode surfaces. Comparison of hematoxylin and eosin, periodic acid-Schiff, and cresyl violet-stained material from the electrode sites with that from other regions did not show any histologic abnormalities attributable to the electrical stimulation. The relatively brief and intermittent periods utilized for human stimulation testing do not appear to cause structural damage at the light microscopic level at charge densities that exceed the threshold for damage established in animal studies with more continuous, chronic stimulation schedules.     

Ultracytochemical demonstration of the polarity of Ca2+-ATPase activity in microglia

In order to investigate plasma membrane Ca²⁺-ATPase (Ca²⁺-ATPase) activity in three subsets of microglia/macrophages (microglia in perineuronal regions (perineuronal microglia)), microglia in contact with the parenchymal side of the vascular basal lamina (juxtavascular microglia) and perivascular cells within the basal lamina), we performed an ultracytochemical study using a lead salt technique in rat cerebral cortices. In 60.6% of perineuronal microglia, the cytochemical reaction (CR) for Ca²⁺-ATPase on the plasma membrane (PM) in the vicinity of neurons was stronger than the CR on the other side of the PM, and deposits of the reaction product (RP) for Ca²⁺-ATPase had accumulated, reflecting the polarity of Ca²⁺-ATPase activity. In contrast, in all of juxtavascular microglia and perivascular cells, deposits of the RP were distributed evenly along the PM without polarity. These results suggest that the polarity of the Ca²⁺-ATPase activity manifests certain functional interactions between perineuronal microglia and neurons.     

Visual information processing after severe closed head injury: effects of forward and backward masking.

Three tachistoscopic tasks were employed to assess whether survivors of severe closed head injury (CHI) exhibit a disturbance of information processing within peripheral and/or central visual pathways. Twelve survivors of severe CHI and 12 individually matched control subjects completed a recognition threshold (no mask) task, a monoptic, forward masking by visual noise task (to assess processing within relatively peripheral pathways), and a dichoptic, backward masking by pattern task (to assess processing within central pathways). For each experimental procedure, the minimum exposure durations required by subjects to identify correctly single consonants and triple consonants were determined. Survivors of severe CHI showed deficits on all three visual tasks. Both groups also had higher threshold durations for the more complex stimuli (triple v single consonants), but differences in threshold were greater in the patients with CHI. The degree of perceptual impairment exhibited by patients with CHI was highly variable and not consistently related to injury characteristics or residual motor or speech and language impairment.     

Studies of dosage, seizure threshold, and seizure duration in ECT

Seizure threshold, defined as the minimal electrical dosage necessary to elicit adequate generalized seizure, was determined throughout the course of electroconvulsive therapy (ECT) in depressed patients randomly assigned to bilateral and right unilateral treatment, with brief pulse, constant current stimulation. In Study 1, it was found that seizure threshold may be more accurately measured using the unit of charge compared to the traditional unit of watt-second. In Study 2, it was found that seizure threshold was associated with seizure duration. Patients with high thresholds had shorter seizure durations. This indicated that the seizure threshold measure assesses in part functional neural activity. In Study 3, it was found that failure for seizure threshold to increase substantially over the course of ECT was associated with poor clinical outcome. In Study 4, it was found that electrical dosage at threshold was not related to magnitude of acute cognitive impairments. This suggested that the degree to which dosage exceeds threshold may be more strongly tied to adverse effects than the absolute dosage administered to patients. Implications of the data are discussed, particularly in relation to a hypothesized link between the anticonvulsant properties of ECT and its mechanism of therapeutic action.     

Seizure susceptibility of neuropeptide-Y null mutant mice in amygdala kindling and chemical-induced seizure models

Neuropeptide Y (NPY) administered exogenously is anticonvulsant, and, NPY null mutant mice are more susceptible to kainate-induced seizures. In order to better understand the potential role of NPY in epileptogenesis, the present studies investigated the development of amygdala kindling, post-kindling seizure thresholds, and anticonvulsant effects of carbamazepine and levetiracetam in 129S6/SvEv NPY(+/+) and NPY(-/-) mice. In addition, susceptibility to pilocarpine- and kainate-induced seizures was compared in NPY(+/+) and (-/-) mice. The rate of amygdala kindling development did not differ in the NPY(-/-) and NPY(+/+) mice either when kindling stimuli were presented once daily for at least 20 days, or, 12 times daily for 2 days. However, during kindling development, the NPY(-/-) mice had higher seizure severity scores and longer afterdischarge durations than the NPY(+/+) mice. Post-kindling, the NPY(-/-) mice had markedly lower afterdischarge thresholds and longer afterdischarge durations than NPY (+/+) mice. Carbamazepine and levetiracetam increased the seizure thresholds of both NPY (-/-) and (+/+) mice. In addition, NPY (-/-) mice had lower thresholds for both kainate- and pilocarpine-induced seizures. The present results in amygdala kindling and chemical seizure models suggest that NPY may play a more prominent role in determining seizure thresholds and severity of seizures than in events leading to epileptogenesis. In addition, a lack of NPY does not appear to confer drug-resistance in that carbamazepine and levetiracetam were anticonvulsant in both wild type (WT) and NPY null mutant mice.     

Effect of electrode size on brain stimulation

Behaviorally determined strength-duration curves of many brain pathways differ from those of peripheral nerves, or single fibers. The chronaxies measured using short-duration pulses are much shorter than those measured with long pulses. A suggested explanation for this was that the pathways have mixed populations of long- and short-chronaxie elements. We attempted to test this hypothesis by stimulating with electrodes of different surface area, on the assumption that they would fire different proportions of long-chronaxie elements at short pulse durations where their thresholds are high. For a given current a large electrode delivers a lower maximum current density than a small one. Electrode size was found to have no detectable effect on the shape of the strength-duration curve. An attempt to discover the characteristics needed to modulate neurons having a basically hyperbolic strength-duration curve so as to produce the empirical curve revealed that the process has a zero rheobase and is thus presumably a direct influence of current on the threshold of the stimulated axons. A probable candidate for this process is the accumulation of potassium iontophoretically driven from cells in the vicinity of the electrode.     

Effects of pulse duration on muscle fatigue during electrical stimulation inducing moderate‐level contraction

Introduction: Neuromuscular electrical stimulation (NMES) is used to prevent muscle atrophy. However, the effect of pulse duration modulation for reducing muscle fatigue and pain is unknown. Methods: Two 2‐minute stimulation protocols were applied to the knee extensors of 10 healthy individuals. In 1 session, a long pulse duration (1,000 μs) and a low current amplitude (LL), set to evoke 25% maximal voluntary contraction at 30 Hz , were applied. The other session was identical except that a short pulse duration (200 μs) and a high current amplitude (SH) were used. Results: Muscle fatigue was lower for LL than for SH (P < 0.01). Force recovery rate was higher for LL than for SH (P < 0.05). Pain scores were also lower for LL than for SH (P < 0.05). Discussion: The use of 1‐ms pulse durations reduces fatigue and pain during NMES for moderate‐level contractions compared with 200‐μs durations. Muscle Nerve 57 : 642–649, 2018