Mechanisms Of High-frequency Stimulation Research Articles

Effects of 10-kHz Subthreshold Stimulation on Human Peripheral Nerve Activation

ObjectiveThe mechanisms of action of high-frequency stimulation (HFS) are unknown. We investigated the possible mechanism of subthreshold superexcitability of HFS on the excitability of the peripheral nerve. Materials and MethodsThe ulnar nerve was stimulated at the wrist in six healthy participants with a single (control) stimulus, and the responses were compared with the responses to a continuous train of 5 seconds at frequencies of 500 Hz, 2.5 kHz, 5 kHz, and 10 kHz. Threshold intensity for compound muscle action potential (CMAP) was defined as intensity producing a 100-μV amplitude in ten sequential trials and “subthreshold” as 10% below the CMAP threshold. HFS threshold was defined as stimulation intensity eliciting visible tetanic contraction. ResultsComparing the threshold of single pulse stimulation for eliciting CMAP vs threshold for HFS response and pooling data at different frequencies (500 Hz–10 kHz) revealed a significant difference (p = 0.00015). This difference was most obvious at 10 kHz, with a mean value for threshold reduction of 42.2%. ConclusionsHFS with a stimulation intensity below the threshold for a single pulse induces axonal superexcitability if applied in a train. It can activate the peripheral nerve and produce a tetanic muscle response. Subthreshold superexcitability may allow new insights into the mechanism of HFS.

Detection of single unit spikes during orthodromic-high frequency stimulation in rat hippocampus.

Deep brain stimulation (DBS) has been used as a treatment of brain diseases such as Parkinson's disease and is a promising therapy for epilepsy. But the mechanisms of high frequency stimulation (HFS) used by DBS are still uncertain. In order to investigate the changes of action penitential firings of individual neurons (single unit activity, SUA) during the period of HFS, a new algorithm based on window detection was designed to detect spikes in broadband-frequency recording signals. The results show that orthodromic-HFS (O-HFS) could excite the neurons in CA1 regions, and the firing rate of interneurons and pyramidal neurons increased significantly. In particular, a decrease in spike amplitude for both interneurons and pyramidal neurons was observed during the period of O-HFS. The amplitude decrease of unit spikes was most remarkable with the presence of HFS-induced population spike (PS). These results suggest that the stimulation pulses of O-HFS could activate the downstream neurons continuously, leading to the downstream neurons being unable to repolarize completely. The results are important for tracking individual neuron activity during HFS and for further understanding of DBS mechanisms.

Biochemical mechanisms of pallidal deep brain stimulation in X-linked dystonia parkinsonism.

Invasive techniques such as in-vivo microdialysis provide the opportunity to directly assess neurotransmitter levels in subcortical brain areas. Five male Filipino patients (mean age 42.4, range 34-52 years) with severe X-linked dystonia-parkinsonism underwent bilateral implantation of deep brain leads into the internal part of the globus pallidus (GPi). Intraoperative microdialysis and measurement of gamma aminobutyric acid and glutamate was performed in the GPi in three patients and globus pallidus externus (GPe) in two patients at baseline for 25/30 min and during 25/30 min of high-frequency GPi stimulation. While the gamma-aminobutyric acid concentration increased in the GPi during high frequency stimulation (231 ± 102% in comparison to baseline values), a decrease was observed in the GPe (22 ± 10%). Extracellular glutamate levels largely remained unchanged. Pallidal microdialysis is a promising intraoperative monitoring tool to better understand pathophysiological implications in movement disorders and therapeutic mechanisms of high frequency stimulation. The increased inhibitory tone of GPi neurons and the subsequent thalamic inhibition could be one of the key mechanisms of GPi deep brain stimulation in dystonia. Such a mechanism may explain how competing (dystonic) movements can be suppressed in GPi/thalamic circuits in favour of desired motor programs.

Computational modeling of Basal Ganglia: towards a mechanism of high frequency stimulation

Deep Brain Stimulation(DBS) with 130Hz represents an effective therapy to alleviate symptoms of some neurodegenerative diseases such as Parkinson syndrome [1]. However the mechanism underlying the observed improvement in patient’s symptoms is still under dispute. Modeling of its mechanism was first done with the Albin-Delong [2] model, which assumed two discriminated feedforward projections, from the input stage Striatum to the output stage Globus pallidus internal (GPi) and Substantia Nigra pars reticulata (SNr). However, this influential contribution neither took motor control into account nor the evidence for a selective of effect high frequency stimulation [3-5]. This study tries to model the underlying network with increasing realistic complexity and presents a spiking network model based on Izhikevich type neurons [6]. Our currently simulated model examines the firing patterns variability between GABAergic STN neuron projections depending on the firing rate. It shows features like synchronous, rythmic population spike found in experimental data of pyramidal interneuronal network [7].

MONOPHASIC BUT NOT BIPHASIC PULSES INDUCE BRAIN TISSUE DAMAGE DURING MONOPOLAR HIGH-FREQUENCY DEEP BRAIN STIMULATION

Electrical high-frequency stimulation (HFS) of deep brain structures has been successfully used as a treatment for patients with movement disorders. The mechanisms of HFS allowing therapeutic clinical effects remain unclear, which justifies experimental studies to address these questions. These experiments require an external stimulator, which may offer the possibility to deliver a current with monophasic or biphasic pulses. The aim of the present study was to quantify the evolution of a potentially deleterious effect of HFS according to the duration and/or intensity in monophasic and biphasic conditions. In all rats, HFS was performed with monophasic pulses in deep brain structures of 1 hemisphere and with biphasic pulses symmetrically in the other hemisphere. The effect of HFS was tested, first for various durations of HFS at a constant intensity (100 microA) and, second, for measuring the effect of various current intensities of HFS at constant duration (10 minutes). At the end of each stimulation test, the volume of lesion was determined and analyzed. In all hemispheres in which stimulation using biphasic pulses was delivered, we never found any relevant lesions. Conversely, monophasic electrical stimulation always created a lesion: at 100 microA, a minimal duration of HFS of 5 minutes induced a tissue damage volume of 0.0055 +/- 0.0015 mm(3). For 10 minutes of HFS, a minimal intensity of 100 microA induced a tissue damage volume of 0.0062 +/- 0.0017 mm(3). Regression analysis showed that the extent of lesion increased linearly with the intensity and duration. In conclusion, this study proved that HFS using monophasic pulses systematically created tissue damage after 5 minutes of stimulation at 100 microA. HFS is safe when biphasic pulses are used for intensities as high as 2 mA and durations as long as 120 minutes. Monophasic pulses can be safely used only during short stimulation and at low intensities.

GABA outflow is modulated by electrical high frequency pulses during N-methyl-D-aspartate receptor activation in the rat caudate nucleus

GABAergic neurons have been demonstrated to play an essential role in the mechanism of high frequency stimulation of deep brain regions, which is an effective treatment in Parkinson's disease. In this study, the effects of electrical high frequency (hf)-pulses and N-methyl-D-aspartate (NMDA) receptor activation on GABA and glutamate outflow were examined in slices of the rat caudate nucleus. Therefore, superfusion experiments were performed and GABA and glutamate outflow were measured by means of HPLC with electrochemical detection after pre-column derivatisation with o-phthaldialdehyde sulphite.