Deep brain stimulation: increasing efficiency by alternative waveforms

Katerina Argiti; Kevin Joseph; Soheil Mottaghi; Thomas J. Feuerstein; Ulrich G. Hofmann

doi:10.1515/cdbme-2016-0034

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Deep brain stimulation: increasing efficiency by alternative waveforms

Katerina Argiti , Kevin Joseph , Soheil Mottaghi , Thomas J. Feuerstein and Ulrich G. Hofmann

Published/Copyright: September 30, 2016

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From the journal Current Directions in Biomedical Engineering Volume 2 Issue 1

Abstract

Deep brain stimulation (DBS) is based on the effect of high frequency stimulation (HFS) in neuronal tissue. As a therapy option for patients suffering from e.g. Parkinson’s disease, DBS has been used for decades. Despite the widespread use, the effect of HFS on neurons is not fully investigated. Improving the stimulation efficiency und specificity could increase the efficiency of the INS (internal neuronal stimulator) as well as potentially reduce unwanted side effects. The effect of HFS on the GABAergic system was quantified using whole cell patch clamp electrophysiology during HFS stimulation in cortical human brain slices in vitro. Rectangular, sine, sawtooth and triangular waveforms were applied extracellularly. Since HFS has been hypothesized to increase the activity of the axons of GABAergic interneurons, a decrease in activity can be observed in the pyramidal cells that the interneurons project to. By isolating the incoming non- GABAergic events, we can filter out only the GABA_A currents which can be verified using a GABA_A antagonist. The results show that all the waveforms effectively increase the GABA_A currents. The triangle waveform causes the highest significant increase in the activity which further increases over time after the stimulation was turned off.

Keywords: deep brain stimulation; GABA; patch clamp; waveforms

1 Introduction

The study of the impact of high frequency electrical stimulation (HFS) on neuronal tissue is one of leading clinical importance. An increasing number of studies underline the positive effect of deep brain stimulation (DBS) on patients suffering from Parkinson’s disease, tremor or dystonia [1], [2], [3]. The procedure includes the implantation of an internal neuronal stimulator (INS). The INS consists of two intracranial electrodes, a connection cable and a pacemaker implanted into the chest. Dependent on the indication, the pulse width varies from 30 to 450 μs and the amplitude from 1 to 5 V. A frequency of 130 Hz is used, in the form of rectangular pulses [4]. These HFS parameters were defined without the subsequently born idea of the mechanism of HFS and are used based on established protocols from decades ago. An improvement in the mode of charge delivery while retaining the same benefits is needed and would at least help increase efficiency of the INS as well as potentially reduce unwanted side effects. Currently, implant’s battery lifetimes are two to seven years, depending on the INS settings [5]. If a battery needs to be replaced, the patient has to endure a small surgical intervention of 20 min. Even though this is only a minor surgery, there are procedural side effects and risks of infections/bleedings. Stimulation dependent side effects are determined by the location of the stimulation and the power of the pulses. If the electrodes are not placed optimal within the target area, non- target cells will be affected by the stimulation and therefore give rise to unwanted side effects. Also, the higher the power of the stimulation pulse, the bigger is the radius of the applied electrical field. By applying a larger field, the chance of activating the non- target cells will be higher and thereby also exacerbates side effects [6], like dysarthria, sensory defects, cramps and double vision [1], [2]. Especially in epilepsy patients where the electrodes are placed in the nucleus anterior thalami (ANT), psychiatric side effects, such as depression, have been observed (SANTE study, [1], [2]). By improving the efficiency of the stimulation, lower amplitudes and smaller pulse widths could be used for achieving the same therapeutic effect and possibly decrease unwanted side effects.

2 Material and methods

Human neocortical tissue was obtained from surgical resections of cortical access tissue during brain tumor surgeries at the University Clinic Freiburg. Every patient was informed and signed a written consent according to the Declaration of Helsinki, as requested by the local Ethics Committee (No 187/04). Tissue from patients with seizures was excluded as well as tissue macroscopically infiltrated with tumor. The tissue was cut to 300 μm slices by a vibratome (Vibrating blade microtome VT1200; Leica, Wetzlar, Germany). The effect of HFS on the GABAergic system was quantified using whole cell patch clamp electrophysiology during HFS stimulation in cortical human brain slices in vitro (Figure 1). Rectangular, sine, sawtooth and triangular waveforms at 130 Hz and a pulse width of 60 μs were applied extracellularly. The stimulations were carried out by a custom built device [7], [8]. The experiment included acquiring whole cell patch of excitatory pyramidal cells in layer 3 of the cortex, with a pause of 5 min after the break in for equilibration of the intracellular solution with the cellular cytosol. The intracellular solution contained the following components (in mM): CsCl 135. NaCl 4, EGTA 0.1, MgCl₂ 2, HEPES 10, TEA 5, QX-314 5, ATP 2, GTP 0.5. The intracellular solution selectively filtered out and blocked all incoming activity except the GABA_A currents. This was verified by the addition of Gabazine, a selective GABA_A antagonist (10 μM) at the end of the experiment to block all the incoming currents into the cell. The recordings were made in voltage clamp mode, with the membrane potential held at −70 mV. A baseline recording of 20 s was made, following which a randomly chosen stimulation was carried out for 20 s following which recordings were made post-stimulation for 40 s. The cells were allowed to rest for 10 min between stimulation to avoid habituation to the stimulation (Figure 2).

Figure 1:

Experimental setup: After patching, there is a 5 min break for the intracellular solution and the cytosol to equilibrate. The stimulation phase consists of three steps: Baseline recording (20 s), stimulation and recording (10 s) and post- stimulation recording (30 s). After the stimulation phase, Gabazine is washed in.

Figure 2:

Whole cell patch clamp and electrical stimulation. The target cells should be in a distance of 500 μm to the stimulation electrode since the optimal electrical field strength is 1 V. When patched, the intracellular solution in the pipette and the cytosol of the cell mix and allow ions to flow in either direction.The pipette-electrode is connected to an operating amplifier, which is grounded and has a feedback resistor.

3 Results

The results show that all the waveforms effectively increase the GABA_A currents (Figure 3). The triangular waveform causes the highest significant increase in the GABA_A currents (141.7 ± 26.17%). Sine and rectangular waveforms show a similar increase in the GABA_A currents (125 ± 22.36% and 128.6 ± 17.55%, respectively). The Sawtooth waveform shows a non-significant increase in the GABA_A currents to 151.1 ± 25.83%. All the stimulation waveforms show a sustained increase in the GABA_A currents even with cessation of the stimulation, at-least for 20 s after the stimulation was stopped. In the post stimulation phase, we see the further increase in the GABA_A current (Table 1).

Figure 3:

Increase in the GABA_A currents. Data is represented in mean values ± SEM expressed in percent of baseline values (=100%). Increase in GABAegic events was seen in all stimulation paradigms, with the most significant increase seen with the triangular waveform. *Represents p < 0.1 compared to baseline values.

Table 1:

Results of the stimulation with different wave forms Numbers in percent.

	Baseline	Stimulation	Post stim
Rectangular	100 ± 14.7	128.6 ± 17.6	150.1 ± 26.7
Sine	100 ± 20.9	125 ± 22.4	152.3 ± 21.41
Sawtooth	100 ± 8.5	151.1 ± 25.8	192.2 ± 45.3
Triangle	100 ± 17.1	141.7 ± 26.2	155.4 ± 20.25

Some cells in every waveform group show very different results to the rest of the cells. These irregularly reacting cells make up 12.5–25% of the investigated cells have to be further investigated and quantified.

4 Discussion

Target tissue of the HFS are axonal structures [9]. Axon terminals from interneurons target glutamatergic pyramidal cells [10]. The GABA release from those terminals causes a chloride inflow which leads to a hyperpolarization of the cell membrane [11], [12]. This so-called inhibitory postsynaptic potential inhibits the emergence of an action potential [12]. Since HFS increases the activity of the axons of GABAergic interneurons [13], a decrease in activity can be observed in the pyramidal cells that the interneurons project to. By isolating the incoming non- GABAergic events, we can filter out only the GABA_A currents, which can be selectively antagonised by Gabazine.

The differences in the outcome of stimulations imply that axons of interneurons, probably the ion channels in those axons themselves, react variedly to different waveforms. Since rectangular is the commonly used waveform for DBS but not the one with the most effective outcome, we can assume that DBS still can be improved significantly. Selectivity and efficiency are two important considerations for the stimulation process. Energy efficiency of the stimulation has a strong relation to the size and life time of the battery [14]. If the efficiency of the stimulation can be increased by choosing a more efficient waveform, lower charges will be needed for generating the same cellular effects on the target area. Also, stimulation charge, wave form, power, and energy may have an effect on the outcome of the stimulated target [6]. Charge efficiency is very important since it can determine the level of tissue damage [15]. Therefore, if alternative, more charge efficient waveforms can be used, the amount of needed charge would decrease and side effects would be less as a result. Concluding it can be stated that not only the waveform but also the placement of the electrodes should be further investigated for increasing battery lifetime and decreasing side effects. Hopefully, patients will have to endure fewer surgeries and can profit from an increase in life quality.

Acknowledgement

The authors would like to acknowledge the BrainLinks-BrainTools, cluster of excellence University of Freiburg. The authors would also like to thank Johanna Kostka for technical support.

Author’s Statement

Research funding: BrainLinks – BrainTools. Conflict of interest: Authors state no conflict of interest. Material and Methods: Informed consent: Informed consent has been obtained from all individuals included in this study. Ethical approval: The research related to human use complies with all the relevant national regulations, institutional policies and was performed in accordance with the tenets of the Helsinki Declaration, and has been approved by the authors’ institutional review board or equivalent committee.

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Published Online: 2016-9-30

Published in Print: 2016-9-1

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https://doi.org/10.1515/cdbme-2016-0034

Keywords for this article

deep brain stimulation; GABA; patch clamp; waveforms

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