Abstract
Electrical stimulation of the subthalamic nucleus (STN) is clinically employed to ameliorate several symptoms of manifest Parkinson’s Disease (PD). Stimulation parameters utilized by chronically implanted pulse generators comprise biphasic rectangular short (60–100 μs) pulses with a repetition frequency between 130 and 180 Hz. A better insight into the effect of electrical stimulation parameters could potentially reveal new possibilities for the improvement of deep brain stimulation (DBS) as a treatment. To this end, we employed single-sided 6-hydroxidopamine (6-OHDA) lesioning of the medial forebrain bundle (MFB) in rats to systematically investigate alternative stimulation parameters. These hemi-parkinsonian (hemi-PD) rats underwent individualized, ipsilateral electrical stimulation to the STN of the lesioned hemisphere, while the transiently induced contralateral rotational behavior was quantified to assess the effect of DBS parameter variations. The number of induced rotations during 30 s of stimulation was strongly correlated with the amplitude of the stimulation pulses. Despite a general linear relation between DBS frequency and rotational characteristics, a plateau effect was observed in the rotation count throughout the clinically used frequency range. Alternative waveforms to the conventional biphasic rectangular (Rect) pulse shapes [Triangular (Tri), Sinusoidal (Sine), and Sawtooth (Lin.Dec.)] required higher charges per phase to display similar behavior in rats as compared to the conventional pulse shape. The Euclidean Distance (ED) was used to quantify similarities between different angular trajectories. Overall, our study confirmed that the effect of different amplitude and frequency parameters of STN-DBS in the hemi-PD rat model was similar to those in human PD patients. This shows that induced contralateral rotation is a valuable readout in testing stimulation parameters. Our study supports the call for more pre-clinical studies using this measurement to assess the effect of other DBS parameters such as pulse-width and interphase intervals.
Highlights
Testing alternative Deep brain stimulation (DBS) parameters in Parkinson’s disease (PD) patients can be challenging for ethical, certification and technical reasons, demanding a more versatile platform to study the biological outcomes of DBS parameters
We used the earlier observation from So et al (2017) that hemiPD animals respond to electrical subthalamic nucleus (STN) stimulation by rotating along their vertical axis – a behavior demonstrated in Figure 1C and usually only seen after chemical stimuli
Neither PW, nor polarity, wave asymmetry or interphase intervals were varied in this study (Stieger et al, 2020)
Summary
Deep brain stimulation (DBS) has matured over the last decades toward a valuable interventional tool to treat a number of neurological and even psychiatric illnesses: Parkinson’s disease (PD) and dystonia have been true ice-breaker applications (Benabid et al, 1991; Tronnier et al, 2002, 2015; Vidailhet et al, 2005; Hardesty and Sackeim, 2007; de Hemptinne et al, 2015), alleviation of chronic pain (Russo and Sheth, 2015) and seizure reduction in epileptics (Velasco et al, 2000; Vonck et al, 2002) were added subsequently. Electrical stimulation is applied to a brain region specific to the disease by implanting noble metal electrodes. Electrical parameters are empirically adjusted to obtain the best treatment outcome. Testing alternative DBS parameters in PD patients can be challenging for ethical, certification and technical reasons, demanding a more versatile platform to study the biological outcomes of DBS parameters
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