Continuous High Frequency Stimulation Research Articles

PS-B05-3: CARDIOVASCULAR RESPONSES EVOKED BY LOW ENERGY CONTINUOUS VERSUS INTERMITTENT STIMULATION OF THE AORTIC BARORECEPTOR AFFERENTS IN HYPERTENSION

Objectives: Device-based neurostimulation of the carotid baroreceptors is a novel approach to control hypertension. We have previously demonstrated the significance of aortic baroreceptor afferent nerves as a viable alternative neuromodulation target to carotid baroreceptors in lowering mean arterial pressure (MAP) in hypertension. We have also shown that appreciable reductions in MAP do not necessarily require the use of ultrahigh stimulation parameters. In this study, we aimed to investigate if energy consumption for neuromodulation of aortic baroreceptor afferents could be lowered further by using intermittent as opposed to continuous stimulation. Design and method: In male anesthetized spontaneously hypertensive rats (SHRs), the effects of continuous (20 sec) versus intermittent (5 sec ON/3 sec OFF and 5 sec ON/5 sec OFF for 20 sec) stimulation of the left aortic depressor nerve (ADN) on MAP, heart rate (HR), mesenteric (MVR) and femoral (FVR) vascular resistance were assessed using low (5 Hz) and high (15 Hz) frequencies delivered at 0.4 mA and 0.2 ms. Results: Continuous and intermittent low frequency stimulation produced similar sustained decreases in MAP, HR, MVR and FVR. Continuous high frequency stimulation produced larger reductions in MAP, HR, MVR and FVR compared with all low frequency and/or intermittent high frequency stimulations. Conclusions: Low charge intermittent stimulation of the aortic baroreceptor afferents maintains the required reductions in MAP levels in hypertension and intermittent delivery of the electrical stimulus can further lower energy consumption for neuromodulation. Clinically, these findings may provide useful insight for studies using baroreflex modulation in resistant hypertension and other cardiovascular diseases.

Low intensity stimulation of aortic baroreceptor afferent fibers as a potential therapeutic alternative for hypertension treatment

Carotid baroreceptor stimulation has been clinically explored for antihypertensive benefits, but neuromodulation of aortic baroreceptor afferents remains unexplored for potential translation into the clinic. Published studies have used supramaximal stimulations, which are unphysiological and energy inefficient. The objective of the present study was to identify optimal low-charge nerve stimulation parameters that would provide a clinically-relevant (20–30 mmHg) decrease in mean arterial pressure (MAP) in anesthetized spontaneously hypertensive rats. Stimulations of 20 s were delivered to the left aortic depressor nerve (ADN) of these rats using low ranges of pulse amplitudes (≤ 0.6 mA), widths (≤ 0.5 ms) and frequencies (≤ 5 Hz). We also assessed the effects of continuous (20 s) versus intermittent (5 s ON/3 s OFF and 5 s ON/3 s OFF for 20 s) stimulation on MAP, heart rate (HR), mesenteric (MVR) and femoral (FVR) vascular resistance using low (5 Hz) and high (15 Hz) frequencies. Lower pulse amplitudes (0.2 mA) produced 9 ± 2 to 18 ± 2 mmHg decreases in MAP. Higher pulse amplitudes (0.4 mA) produced a median MAP reduction of 28 ± 4 mmHg at 0.2 ms and 5 Hz, with no added benefit seen above 0.4 mA. Continuous and intermittent low frequency stimulation at 0.4 mA and 0.2 ms produced similar sustained decreases in MAP, HR, MVR and FVR. Continuous high frequency stimulation at 0.4 mA and 0.2 ms produced larger reductions in MAP, HR, MVR and FVR compared with all low frequency and/or intermittent high frequency stimulations. We conclude from these findings that “low intensity intermittent” electrical stimulation is an effective alternate way for neuromodulation of the aortic baroreceptor afferents and to evoke a required restoration of MAP levels in spontaneously hypertensive rats. This approach enables low energy consumption and markedly lowers the excessive decreases in MAP and hemodynamic disturbances elicited by continuous high-charge injection protocols.

Modulation of inhibitory plasticity in basal ganglia output nuclei of patients with Parkinson's disease

Deep brain stimulation of certain target structures within the basal ganglia is an effective therapy for the management of the motor symptoms of Parkinson's disease. However, its mechanisms, as well as the pathophysiology of Parkinson's disease, are varied and complex. The classical model of Parkinson's disease states that symptoms may arise as a result of increased neuronal activity in the basal ganglia output nuclei due to downregulated GABAergic striato-nigral/-pallidal projections. We sought to investigate the stimulation and levodopa induced effects on inhibitory synaptic plasticity in these basal ganglia output nuclei, and to determine the clinical relevance of altered plasticity with respect to patients' symptoms. Two closely spaced microelectrodes were advanced into the substantia nigra pars reticulata (potential novel therapeutic target for axial motor symptoms) or globus pallidus internus (conventional therapeutic target) in each of 28 Parkinson's disease patients undergoing subthalamic or pallidal deep brain stimulation surgery. Sets of 1 Hz test-pulses were delivered at different cathodal pulse widths (25, 50, 100, 150, 250 μs) in randomized order, before and after a train of continuous high frequency stimulation at 100 Hz. Increasing the pulse width led to progressive increases in both the amplitudes of extracellular focally evoked inhibitory field potentials and durations of neuronal silent periods. Both of these effects were augmented after a train of continuous high frequency stimulation. Additionally, reductions in the baseline neuronal firing rate persisted beyond 1 min after high frequency stimulation. We found greater enhancements of plasticity in the globus pallidus internus compared to the substantia nigra pars reticulata, and that intraoperative levodopa administration had a potent effect on the enhancement of nigral plasticity. We also found that lower levels of nigral plasticity were associated with higher severity motor symptoms. The findings of this study demonstrate that the efficacy of inhibitory synaptic transmission may be involved in the pathophysiology of Parkinson's disease, and furthermore may have implications for the development of novel stimulation protocols, and advancement of DBS technologies.

Continuous High-Frequency Stimulation of the Subthalamic Nucleus Improves Cell Survival and Functional Recovery Following Dopaminergic Cell Transplantation in Rodents

Subthalamic nucleus (STN) high-frequency stimulation (HFS) is a routine treatment in Parkinson’s disease (PD), with confirmed long-term benefits. An alternative, but still experimental, treatment is cell replacement and restorative therapy based on transplanted dopaminergic neurons. The current experiment evaluated the potential synergy between neuromodulation and grafting by studying the effect of continuous STN-HFS on the survival, integration, and functional efficacy of ventral mesencephalic dopaminergic precursors transplanted into a unilateral 6-hydroxydopamine medial forebrain bundle lesioned rodent PD model. One group received continuous HFS of the ipsilateral STN starting a week prior to intrastriatal dopaminergic neuron transplantation, whereas the sham-stimulated group did not receive STN-HFS but only dopaminergic grafts. A control group was neither lesioned nor transplanted. Over the following 7 weeks, the animals were probed on a series of behavioral tasks to evaluate possible graft and/or stimulation-induced functional effects. Behavioral and histological data suggest that STN-HFS significantly increased graft cell survival, graft–host integration, and functional recovery. These findings might open an unexplored road toward combining neuromodulative and neuroregenerative strategies to treat severe neurologic conditions.

2014 Lasker-DeBakey Clinical Medical Research Award.

2014 Lasker-DeBakey Clinical Medical Research Award.

Suppression of acute seizures by theta burst electrical stimulation of the hippocampal commissure using a closed-loop system

This study investigated the effects of electrical stimulation with theta burst stimulation (eTBS) on seizure suppression. Optimal parameters of eTBS were determined through open-loop stimulation experiments and then implemented in a close-loop seizure control system. For the experiments, 4-aminopyridine (4-AP) was injected into the right hippocampus of Sprague–Dawley rats to induce an acute seizure. eTBS was applied on the ventral hippocampal commissure and the effects of eTBS with different combinations of burst frequency and number of pulses per burst were analyzed in terms of seizure suppression. A closed-loop seizure control system was then implemented based on optimal eTBS parameters. The efficiency of the closed-loop eTBS was evaluated and compared to that of high frequency stimulation. The results show that eTBS induced global suppression in the hippocampus and this was sustained even after the application of eTBS. The optimal parameter of eTBS in the open-loop stimulation experiments was a burst frequency at 100Hz with nine pulses in a burst. The eTBS integrated with the on–off control law yielded less actions and cumulative delivered charge, but induced longer after-effects of seizure suppression compared to continuous high frequency stimulation (cHFS). To conclude, eTBS has suppressive effects on 4-AP induced seizure. A closed-loop eTBS system provides a more effective way of suppressing seizure and requires less effort compared to cHFS. eTBS may be a novel stimulation protocol for effective seizure control.

Predicting Outcome in Peripheral Nerve Stimulation for Chronic Neuropathic Pain

The aim of the study was to investigate the predictive value of percutaneous electrical nerve stimulation (PENS) in peripheral nerve stimulation (PNS) for chronic neuropathic pain. Twelve patients being evaluated for PNS for chronic neuropathic pain were included in this survey. Stimulation with acupuncture needles was applied with continuous high frequency stimulation. Position, polarity, frequency and amperage threshold of perception, and adverse effects were noted. Additional stimulation side effects were documented. A StimScore was developed to evaluate effects in a standardized manner. This StimScore comprises coverage of the painful area, therapeutic range, and amperage required for successful stimulation. StimScore was determined during PENS, during test stimulation, and under final stimulation. PNS was well tolerated by all patients. Seven of the 12 patients (58%) were classified as successfully treated, and 5/12 patients (42%) as unsuccessful. The mean overall pain reduction in the first group was 4.0 points (SD = 2.87, P = 0.010) and 2.4 points (SD = 1.29, P = 0.014), respectively, on the visual analogue scale. In the successful stimulation group, a mean StimScore of 13.14 (SD 11.19-15.0) was calculated vs. 10.4 (95% CI 8.52-12.28) in the unsuccessful stimulation group (P = 0.033, 95% CI = 0.265-5.220). Predicting response to PNS is crucial to reduce the number of patients implanted in vain. To adopt PENS via electroacupuncture needles as a percutaneous simulation method for PNS seemed to be feasible. The technique presented herein bears the potential to improve patient selection combined with reduced invasiveness. The presented results are encouraging and deliver a starting point for further trials.

Spike-timing-dependent plasticity steers new Parkinson-stimulation protocols

In advanced Parkinson's disease (PD), deep brain stimulation (DBS) can be used to disrupt pathological activity in the basal ganglia, thereby reducing PD motor symptoms. The standard protocol for DBS, continuous high frequency stimulation of target cells, is applied notably in subthalamic nucleus (STN) or globus pallidus pars interna. It is proposed that short-duration desynchronizing stimulation protocols may also disrupt pathological synchronous activity [1]. Synaptic plasticity is supposed to be the underlying mechanism. The goal of this study is to explore, with a biophysically plausible model, the role of synaptic plasticity in stabilizing firing patterns in the basal ganglia. Moreover, we investigate how STN stimulation should be applied, such that it exploits synaptic plasticity most effectively to bring the network in a less synchronous state.

Characterization of the Left Atrial Neural Network and its Impact on Autonomic Modification Procedures

Left atrial (LA) ganglionated plexi (GP) are part of the intrinsic cardiac autonomic nervous system and implicated in the pathogenesis of atrial fibrillation. High frequency stimulation is used to identify GP sites in humans. The effect of ablation on neural pathways connecting GPs in humans is unknown. Thirty patients undergoing LA ablation with autonomic modification were recruited. In patients with persistent atrial fibrillation, endocardial continuous high frequency stimulation identified GP sites producing AV block. After right lower GP ablation (N=5), 2 of 15 sites remained positive, whereas after ablation of other GPs (N=5), leaving right lower GP intact, all 19 sites remained positive (right lower GP versus other GP, P<0.005), indicating that neural pathways between LAGPs and the AV node are via the right lower GP. In 20 patients with paroxysmal atrial fibrillation, synchronized high frequency stimulation identified sites initiating pulmonary vein (PV) ectopy. After PV isolation (N=8), no sites remained positive. After local GP ablation (N=9), 3 of 14 sites remained positive, suggesting neural connections to the PV were disrupted by both PV isolation and GP ablation. Heart rate variability indices reduced significantly after right upper GP ablation alone, suggesting that neural pathways from the LA to the SA node travel via the right upper GP. We have demonstrated neural pathways connecting LA GPs with the PVs, AV node, and SA node. The effects of high frequency stimulation at GP sites can be prevented by ablating the GP site or the neural pathway. This further delineates the mechanism via which PV isolation prevents atrial fibrillation and highlights important caveats for autonomic modification end points.

A continuous high frequency stimulation of the subthalamic nucleus determines a suppression of excitatory synaptic transmission in nigral dopaminergic neurons recorded in vitro

High frequency stimulation of the subthalamic nucleus (HFS-STN) has been successfully introduced to treat symptoms of advanced Parkinson's disease (PD) (rigidity, tremor and akinesia). In spite of its extensive clinical practice, little is known at cellular level about the effects of a continuous train of electrical stimuli (>100Hz) delivered in the STN. In this manuscript we examine the synaptic responses of substantia nigra pars compacta (SNpc) dopaminergic cells, upon continuous HFS-STN delivered in a rat brain slice preparation.We report that HFS-STN, delivered at frequencies resembling those used during DBS (100–130Hz), caused synaptic responses in SNpc dopaminergic neurons, which summated progressively, until they reached a plateau within few tens of ms. However, if the HFS was maintained, a rapid fading of the synaptic response was observed, with an almost complete loss after 10s. Accordingly, the postsynaptic excitability, evaluated by the tonic firing rate of the SNpc dopaminergic neurons, remained unaltered during a continuous HFS-STN. Upon HFS termination, there was a rapid recovery of synaptic function. Neither a converging synaptic input, evoked by intranigral stimulation, nor the depolarizing responses to locally-applied AMPA, were affected during HFS. The loss of synaptic response by continuous HFS-STN was not prevented by inhibition of AMPA receptor desensitization, nor by antagonists of a variety of neurotransmitter receptors, known to depress synaptic transmission in the SNpc. We conclude that a HFS in the STN, with patterns resembling in vivo DBS, induces a rapid and input-specific suppression of the synaptic transmission from STN to SNpc dopaminergic neurons, that is maintained during an ongoing stimulation. The deficit of transmission between the STN and the SNpc could have a role in the therapeutic effects of the DBS procedure.

The effect of spike time dependent plasticity on activity patterns in the basal ganglia

Background Pathophysiology of Parkinson’s disease (PD) is characterized by increased firing rates of cells in the basal ganglia, a tendency toward bursting and abnormal synchronization in cells of subthalamic nucleus (STN) and globus pallidus pars externa (GPe) [1]. In advanced PD, deep brain stimulation (DBS) can be used to disrupt this pathological activity. The standard protocol for DBS is continuous high frequency stimulation of target cells, such as STN. It has been proposed that short-duration stimulation protocols may also disrupt the pathological activity [2]. The mechanism underlying this protocol is supposedly synaptic plasticity. The goal of this study is to investigate, with a biophysically plausible model, the role of synaptic plasticity in stabilizing firing patterns in the basal ganglia.

Eefcts of the hippocampal deep brain stimulation on cortical epileptic discharges in penicillin –induced epilepsy model in rats

Experimental and clinical studies have revealed that hippocampal DBS can control epileptic activity, but the mechanism of action is obscure and optimal stimulation parameters are not clearly defined. The aim was to evaluate the effects of high frequency hippocampal stimulation on cortical epileptic activity in penicillin-induced epilepsy model. Twenty-five Sprague-Dawley rats were implanted DBS electrodes. In group-1 (n=10) hippocampal DBS was off and in the group-2 (n=10) hippocampal DBS was on (185 Hz, 0.5V, 1V, 2V, and 5V for 60 sec) following penicillin G injection intracortically. In the control group hippocampal DBS was on following 8 μl saline injection intracortically. EEG recordings were obtained before and 15 minutes following penicillin-G injection, and at 10th minutes following each stimulus for analysis in terms of frequency, amplitude, and power spectrum. High frequency hippocampal DBS suppressed the acute penicillin-induced cortical epileptic activity independent from stimulus intensity. In the control group, hippocampal stimulation alone lead only to diffuse slowing of cerebral bioelectrical activity at 5V stimulation. Our results revealed that continuous high frequency stimulation of the hippocampus suppressed acute cortical epileptic activity effectively without causing secondary epileptic discharges. These results are important in terms of defining the optimal parameters of hippocampal DBS in patients with epilepsy.

Skeletal muscle fatigue is caused by either e‐c coupling, metabolic alterations mechanisms or both

Muscle fatigue may be due to a failure in excitation‐contraction coupling or an increase of ATP by products and NO. E‐c coupling alterations occur earlier and metabolic alterations take place later. We investigated these possibilities in frog skeletal muscle by continuous high frequency stimulation and different periods of repetitively stimulations. We judged the extent of e‐c or metabolic possibilities by releasing Ca2+ with 5 mM caffeine prior and immediately after fatigue.Continuously 60 Hz electric stimulations produced a force dropped to 0.33 ± 0.05 SD the control tetanus force, within a few seconds. The ratio of caffeine force development after and before fatigue was 1.02 ± 0.24 SD. This indicated that the interaction of myosin with actin was not impaired. After repetitive stimulation, the force dropped to 0.85 ± 0.04 SD (6 tetani) and 0.65± 0.11 SD (24 tetani) the control tetanus. Here, the ratio of caffeine force after and before fatigue development was 0.75 ± 0.3 SD. The concentration of caffeine used was the same as before therefore the acto‐myosin interaction was impaired during prolonged repetitive stimulations. The two types of fatigue take place.

Continuous high-frequency stimulation in freely moving rats: Development of an implantable microstimulation system

High-frequency stimulation (HFS) of basal ganglia and thalamic nuclei is an established treatment for various movement disorders and has recently been extended to other neuro-psychiatric conditions. Numerous experimental studies in small laboratory animals provided important insights in the mode of action of HFS. However, the interpretation of the results is often limited by the use of short-term HFS, while patients receive continuous stimulation for many years. One reason is the lack of an established model for the application of long-term HFS in small animals. Therefore, we thought to develop an implantable microstimulation system for small laboratory animals and to establish a protocol for long-term HFS by defining non-damaging stimulus parameters with respect to brain integrity. For this purpose, we designed a miniaturized, microcontroller-based, and programmable microstimulator that allows the reliable application of continuous HFS for up to 5 weeks. Chronic HFS (total stimulation time: 3 weeks) of the subthalamic nucleus with up to 100 μA (5.2 nC/phase) through monopolar electrodes comprising activated iridium did not induce significant tissue damage as assessed by various histological techniques (Nissl's, hematoxylin and eosin, Klüver-Barrera, van Gieson's staining, NeuN and GFAP-immunoreactivity). In conclusion, chronic HFS with an implantable stimulator can be successfully applied in small animals.

Effect of low and high frequency thalamic stimulation on sleep in patients with Parkinson's disease and essential tremor.

Continuous high frequency stimulation of the ventral intermediate nucleus of the thalamus (Vim), delivered through surgically implanted quadripolar electrodes, alleviates tremor in Parkinson's disease (PD) and essential tremor (ET). The Vim is adjacent to the thalamic reticular nuclei, where sleep spindles originate according to animal models. In order to determine whether Vim stimulation affects sleep spindles, six patients (4 PD, 2 ET), aged 60-69 years, were recorded on a control night and a stimulation night (130 Hz, 2-3 V; right stimulation in five patients and bilateral stimulation in one patient). Stimulation did not modify sleep quality or architecture. Sleep spindles were present and symmetrical in five out of six patients under stimulation. However, in one patient with a sustained 'thalamotomy-like effect' that abolished tremor, spindles were asymmetrical even without stimulation. In each patient, spindle density was similar on both nights (mean+/- SEM: 2.25+/-0. 61 spindles per min of stage 2 sleep vs. 1.84+/-0.31). In an attempt to promote sleep two different patterns of stimulation were applied in the region of ventrooralis posterior and reticularis nuclei in five patients in the awake state. Continuous low frequency stimulation (5 Hz, 0.1 V), and repeated trains of 15 Hz for 1 s every 15 s mimicking the pattern of physiological spindles, each failed to induce sleep or cortical synchronization. We conclude that Vim stimulation, unlike thalamotomy, selectively reduces tremor without altering sleep or sleep spindles. Our results also suggest that low frequency stimulation applied in the region of the reticular nuclei does not induce sleep.

Transcutaneous electrical nerve stimulation: A microneurographic and perceptual study

With the aim of studying peripheral physiological mechanisms involved in transcutaneous electrical nerve stimulation (TENS) for the suppression of pain, the authors have examined 14 healthy volunteers in the perceptual part and 8 in the microneurographic part of this study. For pain suppressing stimulation they have used ring electrodes and stimulators capable of producing rectangular, sine wave, triangular and hybrid wave forms. Pain was induced with electrical stimuli on the distal phalanx of the middle finger. TENS with rectangular, sine wave and triangular pulses activates mainly Aβ, but also some Aδ fibres. Pain suppressing capacity of different wave forms used was the same and was achieved with stimuli close to the threshold for pain. Pain was most effectively dimished when noxious and pain suppressing stimuli were applied to the same finger; this effect was smaller with the two stimuli on neighbouring fingers and very weak when pain suppressing stimulus was applied to the contralateral hand. Increases in stimulus frequency resulted in an increased and variable latency as well as intermittent blocking of those spike components which had been near threshold at low frequency stimulation. This is interpreted as being due to local changes in excitation threshold. In surface-recorded averaged electroneurograms this effect was seen as amplitude decrement and increased response duration, but was not due to impulse transmission failure in Aδ fibres as seen microneurographically. On continuous high frequency stimulation, the intensity of sensation elicited diminished, although there was no change in the microneurogram. The authors conclude that the peripheral contribution to the analgesic effects of TENS seems to be unimportant.

Effect of hemicholinium-3 on the release and net synthesis of acetylcholine in Auerbach's plexus of guinea pig ileum

The amount of acetylcholine released from innervated longitudinal muscle of the guinea-pig ileum evoked by continuous high frequency stimulation reached a peak value of 952.3 pmol · g −1 followed by a gradual decrease and formation of a new equilibrium state (568.4 pmol · g −1· min −1), which probably corresponded to the rate of synthesis. Hemicholinium-3 at a concentration of 10 −6m did not inhibit the instantaneous release of acetylcholine neither from the stimulated nor from the non-stimulated organ, but completely prevented the establishment of a new equilibrium state. Although 50–70% of the acetylcholine content was still present in the tissues treated with hemicholinium-3, both the stimulation-induced and resting release was abolished. It is concluded that this part of the acetylcholine content is not available for release. When calculating the net synthesis of acetylcholine in hemicholinium-3 treated organs, 37.1 nmol · g −1 acetylcholine was missing, i.e. the synthesis was not only blocked but decomposition of acetylcholine occurred. The amount of decomposed (‘lost’) acetylcholine was identical both in stimulated and non-stimulated strips. It is suggested that backward reaction of choline acetyltransferase is responsible for this phenomenon.

Properties of the olfactory efferent system.

SUMMARYAppropriately timed afferent stimulation of one olfactory bulb can depress afferent induced activity in the opposite bulb, the depression being mediated by the true commissural component of the anterior commissure which is part of the olfactory efferent system. Bulbar retrograde responses evoked by lateral olfactory tract stimulation are depressed by continuous high frequency stimulation of the anterior commissure, and this is considered to be further evidence for a depressive action of the efferent system in the olfactory bulb. Stimulation of the efferent system evokes monophasic negative waves in the bulb which, on continuous stimulation, summate to give a sustained negativity. The appearance of this negative shift is correlated with the onset of the depressive influence. Lateral olfactory tract stimulation evokes polyphasic, dominantly positive, waves in the bulb which do not summate but rapidly fatigue on repetitive stimulation at high frequencies.