High-frequency Pulse Trains Research Articles

Coordinated reset has sustained aftereffects in Parkinsonian monkeys

Coordinated reset neuromodulation consists of the application of consecutive brief high-frequency pulse trains through the different contacts of the stimulation electrode. In theoretical studies, by achieving unlearning of abnormal connectivity between neurons, coordinated reset neuromodulation reduces pathological synchronization, a hallmark feature of Parkinson's disease pathophysiology. Here we show that coordinated reset neuromodulation of the subthalamic nucleus has both acute and sustained long-lasting aftereffects on motor function in parkinsonian nonhuman primates. Long-lasting aftereffects were not observed with classical deep brain stimulation. These observations encourage further development of coordinated reset neuromodulation for treating motor symptoms in Parkinson disease patients.

Pentobarbital inhibition of human recombinant α1A P/Q‐type voltage‐gated calcium channels involves slow, open channel block

Pre-synaptic neurotransmitter release is largely dependent on Ca(2+) entry through P/Q-type (Ca(V)2.1) voltage-gated Ca(2+) channels (PQCCs) at most mammalian, central, fast synapses. Barbiturates are clinical depressants and inhibit pre-synaptic Ca(2+) entry. PQCC barbiturate pharmacology is generally unclear, specifically in man. The pharmacology of the barbiturate pentobarbital (PB) in human recombinant alpha(1A) PQCCs has been characterized. PB effects on macroscopic Ca(2+)(I(Ca)) and Ba(2+)(I(Ba)) currents were studied using whole-cell patch clamp recording in HEK-293 cells heterologously expressing (alpha(1A))(human)(beta(2a)alpha(2)delta-1)(rabbit) PQCCs. PB reversibly depressed peak current (I(peak)) and enhanced apparent inactivation (fractional current at 800 ms, r(800)) in a concentration-dependent fashion irrespective of charge carrier (50% inhibitory concentration: I(peak), 656 microM; r(800), 104 microM). Rate of mono-exponential I(Ba) decay was linearly dependent on PB concentration. PB reduced channel availability by deepening non-steady-state inactivation curves without altering voltage dependence, slowed recovery from activity-induced unavailable states and produced use-dependent block. PB (100 microM) induced use-dependent block during physiological, high frequency pulse trains and overall depressed PQCC activity by two-fold. The results support a PB pharmacological mechanism involving a modulated receptor with preferential slow, bimolecular, open channel block (K(d)= 15 microM). Clinical PB concentrations (<200 microM) inhibit PQCC during high frequency activation that reduces computed neurotransmitter release by 16-fold and is comparable to the magnitude of Ca(2+)-dependent facilitation, G-protein modulation and intrinsic inactivation that play critical roles in PQCC modulation underlying synaptic plasticity. The results are consistent with the hypothesis that PB inhibition of PQCCs contributes to central nervous system depression underlying anticonvulsant therapy and general anaesthesia.

High frequency pulse trains from a self-starting additive pulse mode-locked all-fiber laser

Abstract In this paper, a coupled-cavity Er-doped fiber laser is experimentally developed and analyzed. The proposed scheme has the advantage of an all-fiber configuration. Two similar fiber Bragg gratings are employed as reflective components of the main cavity containing the gain medium. The second cavity is generated, in one side, by the reflective flat end of a standard fiber optic pigtail of variable length and, in the other, by one of the Bragg gratings belonging to the main cavity. Depending on the ratio between the lengths of both cavities, trains of stable and short pulses were obtained with a repetition frequency larger than the frequency of the main cavity. The repetition rate of the pulse trains experimentally obtained was as high as 780 MHz (15 times the main cavity frequency) and the pulse width was ∼110 ps. Prediction of the possible repetition rates for each cavities lengths ratio and the upgrading possibilities of this laser system are analyzed.

Influence of Temperature on Pudendal Nerve Block Induced by High Frequency Biphasic Electrical Current

We determined the influence of temperature on the minimal stimulation frequency required to block pudendal nerve conduction. The pudendal nerve block induced by high frequency, biphasic electrical current was investigated at different temperatures using cats under alpha-chloralose anesthesia. Urethral pressure was measured to indicate pudendal nerve activation or block. As stimulation frequency was increased above a frequency threshold, the urethral pressure response was decreased and the pudendal nerve was blocked. The minimal stimulation frequency required to block the pudendal nerve was decreased from 6 to 4 kHz as the temperature was decreased from 37C to 15C. At a 4 kHz frequency the maximal temperature below which the pudendal nerve could be blocked was 24.5C. To block pudendal nerve conduction at body temperature (37C) the stimulation frequency must be greater than 6 kHz. This study provides a practical guide for blocking the pudendal nerves to restore efficient voiding after spinal cord injury.

Tremor entrainment by patterned low-frequency stimulation

High-frequency test stimulation for tremor suppression is a standard procedure for functional target localization during deep brain stimulation. This method does not work in cases where tremor vanishes intraoperatively, for example, due to general anaesthesia or due to an insertional effect. To overcome this difficulty, we developed a stimulation technique that effectively evokes tremor in a well-defined and quantifiable manner. For this, we used patterned low-frequency stimulation (PLFS), i.e. brief high-frequency pulse trains administered at pulse rates similar to neurons' preferred burst frequency. Unlike periodic single-pulse stimulation, PLFS enables one to convey effective and considerably greater integral charge densities without violation of safety requirements. In a computational investigation of an oscillatory neuronal network temporarily rendered inactive, we found that PLFS evokes synchronized activity, phase locked to the stimulus. While a stronger increase in the amount of synchrony in the neuronal population requires higher stimulus intensities, the portion of synchronously active neurons nevertheless becomes strongly phase locked to PLFS already at weak stimulus intensities. The phase entrainment effect of PLFS turned out to be robust against variations in the stimulation frequency, whereas enhancement of synchrony required precisely tuned stimulation frequencies. We applied PLFS to a patient with spinocerebellar ataxia type 2 (SCA2) with pronounced tremor that disappeared intraoperatively under general anaesthesia. In accordance with our computational results, PLFS evoked tremor, phase locked to the stimulus. In particular, weak PLFS caused low-amplitude, but strongly phase-locked tremor. PLFS test stimulations provided the only functional information about target localization. Optimal target point selection was confirmed by excellent post-operative tremor suppression.

Preface

Preface

Pulse-Train Stimulation for Detecting Medial Malpositioning of Thoracic Pedicle Screws

Thoracic pedicle screw location and the current needed to stimulate adjacent neural tissue was evaluated using brief, high-frequency pulse trains and monitoring electromyography (EMG) from muscles in the lower limbs. To establish a safe and reliable method for detecting medial malpositioning of pedicle screws placed in the thoracic spine during instrumentation and fusion. Neurophysiologic studies for testing thoracic pedicle screw placement used single-pulse stimulation and monitored EMG from thoracic-innervated muscles. We propose that with this approach, stimulation fails to activate lower motor neurons innervated by spinal cord axons, such that medial malplacement of screws will go largely undetected. EMG was monitored from multiple lower-limb muscles. Pedicle tracks were created free-hand, using a curved pedicle finder. A ball-tipped probe-insulated along its shaft-was used to palpate the walls of the pedicle tracks. During probing, constant-current, high-frequency 4-pulse stimulus trains were delivered through the ball tip, and the minimum current (i.e., threshold) needed to evoke EMG was determined for each pedicle track. The threshold current for stimulation through each screw was also determined. Postoperative serial computed tomography scans of all implanted thoracic and L1 screws were rated with respect to screw position and the pedicle wall. A total of 116 screws were implanted in 7 subjects. Two pedicle tracks were redirected during surgery because of particularly low thresholds to stimulation. Definite medial defects were found in 19 screws, 18 of which were detected by the experimental technique. For these screws, the average threshold to probe stimulation of their associated pedicle tracks was 7.9 +/- 4.6 mA, much lower than current thresholds for less medially placed pedicle tracks. Stimulation of these screws resulted in high thresholds (19.8 +/- 5.3 mA) when a response was evoked at all; stimulating 8 of these 19 medially malpositioned screws failed to elicit any lower-limb EMG at considerably higher (25 or 30 mA) stimulus intensities. This preliminary study supports the hypothesis that high-frequency stimulus pulse trains areeffective at detecting defects in the medial wall of pedicles in the thoracic spine during instrumentation, thereby improving on techniques using single-pulse stimulus protocols.

Optimal deep brain stimulation of the subthalamic nucleus—a computational study

Deep brain stimulation (DBS) of the subthalamic nucleus, typically with periodic, high frequency pulse trains, has proven to be an effective treatment for the motor symptoms of Parkinson's disease (PD). Here, we use a biophysically-based model of spiking cells in the basal ganglia (Terman et al., Journal of Neuroscience, 22, 2963-2976, 2002; Rubin and Terman, Journal of Computational Neuroscience, 16, 211-235, 2004) to provide computational evidence that alternative temporal patterns of DBS inputs might be equally effective as the standard high-frequency waveforms, but require lower amplitudes. Within this model, DBS performance is assessed in two ways. First, we determine the extent to which DBS causes Gpi (globus pallidus pars interna) synaptic outputs, which are burstlike and synchronized in the unstimulated Parkinsonian state, to cease their pathological modulation of simulated thalamocortical cells. Second, we evaluate how DBS affects the GPi cells' auto- and cross-correlograms. In both cases, a nonlinear closed-loop learning algorithm identifies effective DBS inputs that are optimized to have minimal strength. The network dynamics that result differ from the regular, entrained firing which some previous studies have associated with conventional high-frequency DBS. This type of optimized solution is also found with heterogeneity in both the intrinsic network dynamics and the strength of DBS inputs received at various cells. Such alternative DBS inputs could potentially be identified, guided by the model-free learning algorithm, in experimental or eventual clinical settings.

P6-94: Hemodynamic effects of coupled pacing with high-frequency pulse trains in the porcine heart

P6-94: Hemodynamic effects of coupled pacing with high-frequency pulse trains in the porcine heart

High repetition rate pulses generated by differential phase assisted injection-locking of Fabry–Perot laser diode

We demonstrate a novel method for generating optical pulses at 10 and 20 GHz using differential phase assisted (DPA) injection-locking of a Fabry–Perot laser diode (FP-LD). High frequency pulse-trains were generated from low-frequency specification FP-LD. The time-bandwidths of the pulses were 0.302 and 0.404 for the 10 and 20 GHz pulse-trains, respectively. The stability and noise performance of the output pulses are characterized and we show that the pulse-trains have less phase and amplitude noise than those produced from directly modulated laser diode.

Desynchronization of electrically evoked auditory-nerve activity by high-frequency pulse trains of long duration.

Rubinstein et al. [Hear. Res. 127, 108-118 (1999)] suggested that the neural representation of the waveforms of electric stimuli might be improved by introducing an ongoing, high-rate, desynchronizing pulse train (DPT). A DPT may desynchronize neural responses to electric stimulation in a manner similar to spontaneous activity in a healthy ear. To test this hypothesis, responses of auditory-nerve fibers (ANFs) to 10-min-long electric pulse trains (5 kpps) were recorded from acutely deafened, anesthetized cats. Stimuli were delivered via an intracochlear electrode, and their amplitude was chosen to elicit a response in most ANFs. Responses to pulse trains showed pronounced adaptation during the first 1-2 min, followed by either a sustained response or cessation of spike discharges for the remainder of the stimulus. The adapted discharge rates showed a broad distribution across the ANF population like spontaneous activity. However, a higher proportion of fibers (46%) responded to the DPT at rates below 5 spikes/s than for spontaneous activity, and 12% of the fibers responded at higher rates than any spontaneously active fiber. Interspike interval histograms of sustained responses for some fibers had Poisson-like (exponential) shapes, resembling spontaneous activity, while others exhibited preferred intervals and, occasionally, bursting. Simultaneous recordings from pairs of fibers revealed no evidence of correlated activity, suggesting that the DPT does desynchronize the auditory nerve activity. Overall, these results suggest that responses to an ongoing DPT resemble spontaneous activity in a normal ear for a substantial fraction of the ANFs.

STIMULATION FREQUENCY ALTERS RATE OF FORCE DEVELOPMENT

At sub-tetanic stimulation frequencies, muscles partially relax in the time between consecutive stimuation pulse. It is generally assumed that the tetanic stimulation frequency does not provide enough time for muscle relaxation between pulses. However, it is well known that a short series of relatively high frequency stimulation pulses (e.g. “doublet”) at the beginning of a stimuation pulse train increases the rate of force development (df/dt) relative to a pulse train at the tetanic frequency. We hypothesized that the brief high frequency pulse train acts to prevent relaxation wthin the interpulse interval. Purpose The purpose of this investigation was to determine the effects of stimulation frequency on maximum force and maximum df/dt and to determine if partial relaxation occurred at or above tetanic stimulation frequency. Methods The gastrocnumious of Syrian Golden Hamsters (N=5) was stimulated in situ for 250ms at 30 to 200hz via the sciatic nerve. Maximum force and maximum df/dt were determined for each frequency. Fourier analyses were performed to determine if the stimulation frequency influenced the frequency content of the force or df/dt signal. Results Maximum force increased to a peak at approximately 100hz and declined with further increases in stimulation frequency. Maximum df/dt increased across all frequencies. The stimulation frequency was evident within the df/dt signal at all frequencies. Conclusions Based on these data, we conclude that inter-pulse relaxation of muscle occurs in as little as 5ms in this mixed fiber type muscle (approximately 70% fast twitch). These data support our hypothesis and suggest that high frequency stimulation trains allows higher df/dt by minimizing inter-pulse relaxation during force development. Supported by ALA RG-013N

All-optical coding of mode-locked semiconductor laser pulse trains for high bit rate optical communications

We demonstrate an all-optical scheme for coding high frequency mode-locked semiconductor laser pulse trains. The scheme is experimentally demonstrated by optically modulating a high frequency pulse train at 38 GHz generated by a subharmonic synchronous mode-locked semiconductor laser with binary information contained in multiple low bit rate optical data signals (3.8 Gb/s). Synchronization between the two signals is achieved through optical injection into the mode-locked laser while high speed modulation is achieved via a nonlinear optical loop mirror made of dispersion shifted fiber. The coding scheme has advantages over existing passive multiplexing schemes in generating high data rate optical signals due to its regeneration and wavelength conversion functionality.

Functional characterization of the D188V mutation in neuronal voltage-gated sodium channel causing generalized epilepsy with febrile seizures plus (GEFS)

Mutations in the alpha 1 subunit of the voltage-gated sodium channel ( SCN1A) have been increasingly recognized as an important cause of familial epilepsy in humans. However, the functional consequences of these mutations remain largely unknown. We identified a mutation (D188V) in SCN1A segregating with generalized epilepsy with febrile seizures (GEFS) in a large kindred. Compared to wild-type sodium channels, in vitro expression of channels harboring the D188V mutation were found to be more resistant to the decline in amplitude that is normally observed over the course of high frequency pulse trains. This small change on a single aspect of channel function is compatible with an increase in membrane excitability, such as during sustained and uncontrolled neuronal discharges. These data suggest that this specific effect on sodium channel function could be a general mechanism in the pathophysiology of epilepsies caused by mutations in sodium channels in humans.

Desynchronization by Means of a Coordinated Reset of Neural Sub-Populations

The coordinated reset of neural sub-populations is introduced as an effectively desynchronizing stimulation technique. For this, short sequences of high-frequency pulse trains are administered at different sites in a coordinated way, i.e. separated by suitable fixed delays. Desynchronization is effectively maintained by performing a coordinated reset with demand-controlled timing or by periodically administering resetting high-frequency pulse trains of demand-controlled length. Unlike previously developed methods, this novel approach is robust against variations of model parameters, and does not require time-consuming calibration. I suggest the novel technique to be used for demand-controlled deep brain stimulation in patients suffering from Parkinson's disease or essential tremor. Furthermore, the novel stimulation method might even be applicable to diseases with intermittently emerging synchronized neural oscillations like epilepsy.

Thalamic-Evoked Synaptic Interactions in Barrel Cortex Revealed by Optical Imaging

We used optical imaging of voltage-sensitive dye signals to study the spatiotemporal spread of activity in the mouse barrel cortex, evoked by stimulation of thalamocortical afferents in an in vitro slice preparation. Stimulation of the thalamus, at low current intensity, results in activity largely restricted to a single barrel, and to the border between layers Vb and VI. Low concentrations of the GABA(A) receptor antagonist bicuculline increase the amplitude of the optical signals, without affecting their spatiotemporal propagation. Higher concentrations of bicuculline result in paroxysmal activity, which propagates via intracolumnar and intercolumnar excitatory pathways. Enhancing the activity of NMDA receptors, by removing Mg(2+) from the extracellular solution, dramatically alters the spatiotemporal pattern of excitation: activity spreads to supragranular and infragranular layers and adjacent barrel columns. This enhanced propagation is suppressed by the NMDA receptor antagonist AP5. A similar enhancement of activity propagation can be produced by stimulating the thalamus with a short, high-frequency pulse train. Application of AP5 suppresses the frequency-dependent spread of activity. These findings indicate that the spatiotemporal spread of activity in the barrel cortex is altered by varying the temporal patterns of thalamic inputs, via an NMDA receptor-mediated mechanism, and suggest that a similar process occurs during repetitive whisking activity.

C-Fos expression in the basilar pontine nuclei and reticulotegmental nucleus of the rat following lateral cerebellar nucleus stimulation.

The present study was carried out with the aim to observe whether, in the rat, the electric activation of the projection form the cerebellar lateral nucleus (LN) to the basilar pontine nuclei (BPN) and to the reticulotegmental nucleus (RtTg) is capable to induce the c-Fos expression. In particular, we compared the effects of a continuous LN stimulation at low-frequency (tonic stimulation) with those induced by high frequency pulse trains (phasic stimulation). The observed results show that the stimulation of LN induces c-Fos expression in a significant fraction of neurons in the contralateral BPN and RtTg. It was also observed that phasic stimulation was slightly more capable in producing c-Fos expression with respect to the tonic stimulation. Furthermore, systemic injection of MK-801, a non-competitive antagonist of the NMDA receptor, reduced the LN-induced c-Fos expression in BPN and RtTg. In contrast, GYKI 52466, an AMPA/kainate receptor antagonist, did not change the LN driven induction of c-Fos in both BPN and RtTg.

C-fos expression in the accessory oculomotor nuclei following neocerebellar stimulation.

The present study was carried out to determine whether, in the rat, the electric activation of the projection from the cerebellar lateral nucleus (LN) to the accessory oculomotor nuclei (AON; nucleus of posterior commissure, nucleus of Darkschewitsch, interstitial nucleus of Cajal) is capable of inducing c-fos expression. In particular, we compared the effects of a continuous LN stimulation at low-frequency (tonic stimulation) with those induced by high frequency pulse trains (phasic stimulation). The observed results show that the stimulation of LN induces c-fos expression in a significant proportion of neurones in the contralateral AON. Phasic stimulation was slightly more effective than tonic stimulation in producing c-fos expression.

Effect of opioid receptor subtype‐selective agonists on purinergic and adrenergic components of neurogenic contractions of mouse vas deferens

1. Effects of opioid agonists on the purinergic and adrenergic components of neurogenic contractions and in some experiments on transmitter overflow were studied in the mouse isolated vas deferens. 2. When the vas deferens was stimulated every 2 min by pairs of pulses 2 s apart in the presence of prazosin 0.3 microM (to isolate the purinergic component) or alpha,beta-methylene-ATP 3 microM (to isolate the adrenergic component), each pulse elicited a separate twitch. The opioid agonists [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin (DAMGO, mu-receptor-selective), [D-Pen2,D-Pen5]enkephalin (DPDPE, delta-selective) and trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]- benzeneacetamide (U-50488, kappa-selective) concentration-dependently reduced both purinergic and adrenergic contractions. For each agonist, maximal effects and concentrations causing half-maximal effects were very similar for inhibition of the purinergic component on the one hand and for inhibition of the adrenergic component on the other hand, although the adrenergic component was inhibited with a slight preference. Moreover, effects on contractions elicited by the first and the second pulse of the pairs were very similar. 3. When vasa deferentia preincubated with [3H]-noradrenaline were stimulated with trains of 100 pulses delivered at 20 Hz, morphine 10 microM reduced significantly both evoked tritium overflow and evoked contractions. Its effect was antagonized by naloxone. 4. It is concluded that, in contrast to drugs acting at some other presynaptic receptors, opioid mu-, delta- and kappa-agonists inhibit purinergic and adrenergic neurogenic contractions of the mouse vas deferens in a similar manner. In contrast to a previous report, no enhancement by morphine of the release of noradrenaline elicited by high frequency pulse trains was observed.

HIGH RESOLUTION MONOPULSE RADAR TRACKING SYSTEM

High resolution radar techniques are applied to the problem of resolving a multiple target array and locating its geometric center without the usual biasing toward the brightest scatterer. This result is accomplished using monopulse radar techniques combined with high resolution stepped frequency pulse train signal processing in an angle tracking noncoherent high resolution radar. The center of each uniquely separated pair of point targets is calculated by examining the crosscorrelation function of the sum and difference channels. The autocorrelation of the sum channel is used to normalize the crosscorrelation data thereby eliminating the effects of the different targets’ radar cross sections (RCS). The zero separation term of the error function (dc term) remains biased toward the bigger scatterer, even after normalization. The nonzero terms (ac terms) are the cross range distances from the antenna’s boresight to each scatterer and are independent of their RCS. By simply dropping the zero separation term and averaging the remaining terms together, the aimpoint becomes the unbiased geometric center of the array.