Dennis T. T. Plachta

Blood pressure control with selective vagal nerve stimulation and minimal side effects

OBJECTIVE Hypertension is the largest threat to patient health and a burden to health care systems. Despite various options, 30% of patients do not respond sufficiently to medical treatment. Mechanoreceptors in the aortic arch relay blood pressure (BP) levels through vagal nerve (VN) fibers to the brainstem and trigger the baroreflex, lowering the BP. Selective electrical stimulation of these nerve fibers reduced BP in rats. However, there is no technique described to localize and stimulate these fibers inside the VN without inadvertent stimulation of non-baroreceptive fibers causing side effects like bradycardia and bradypnea. APPROACH We present a novel method for selective VN stimulation to reduce BP without the aforementioned side effects. Baroreceptor compound activity of rat VN (n = 5) was localized using a multichannel cuff electrode, true tripolar recording and a coherent averaging algorithm triggered by BP or electrocardiogram. MAIN RESULTS Tripolar stimulation over electrodes near the barofibers reduced the BP without triggering significant bradycardia and bradypnea. The BP drop was adjusted to 60% of the initial value by varying the stimulation pulse width and duration, and lasted up to five times longer than the stimulation. SIGNIFICANCE The presented method is robust to impedance changes, independent of the electrodes relative position, does not compromise the nerve and can run on implantable, ultra-low power signal processors.

Effect of selective vagal nerve stimulation on blood pressure, heart rate and respiratory rate in rats under metoprolol medication

Selective vagal nerve stimulation (sVNS) has been shown to reduce blood pressure without major side effects in rats. This technology might be the key to non-medical antihypertensive treatment in patients with therapy-resistant hypertension. β-blockers are the first-line therapy of hypertension and have in general a bradycardic effect. As VNS itself can also promote bradycardia, it was the aim of this study to investigate the influence of the β1-selective blocker Metoprolol on the effect of sVNS especially with respect to the heart rate. In 10 male Wistar rats, a polyimide multichannel-cuff electrode was placed around the vagal nerve bundle to selectively stimulate the aortic depressor nerve fibers. The stimulation parameters were adapted to the thresholds of individual animals and were in the following ranges: frequency 30–50 Hz, amplitude 0.3–1.8 mA and pulse width 0.3–1.3 ms. Blood pressure responses were detected with a microtip transducer in the carotid artery, and electrocardiography was recorded with s.c. chest electrodes. After IV administration of Metoprolol (2 mg kg−1 body weight), the animals’ mean arterial blood pressure (MAP) and heart rate (HR) decreased significantly. Although the selective electrical stimulation of the baroreceptive fibers reduced MAP and HR, both effects were significantly alleviated by Metoprolol. As a side effect, the rate of stimulation-induced apnea significantly increased after Metoprolol administration. sVNS can lower the MAP under Metoprolol without causing severe bradycardia.

Detection of baroreceptor activity in rat vagal nerve recording using a multi-channel cuff-electrode and real-time coherent averaging

Electrical stimulation of afferent nerve fibers originating from pressure sensors can trigger the baroreflex to reduce blood pressure and might be an alternative to treat patients with hypertension. In this study, baroreceptor compound activity was detected using multi-channel cuff-electrode recordings on rat vagal nerve. In order to isolate the vagal nerve signals from external potentials (such as ECG- and EMG-coupling), a tripolar measuring technique was applied. To eliminate noise and neural signals corresponding to other organs, coherent averaging was used. The baroreceptor-correlated signals appear predominantly in one of the electrode channels, presumably close to the corresponding neural substrate. This localization was done in real-time.

Miniaturized neural interfaces and implants

Neural prostheses are technical systems that interface nerves to treat the symptoms of neurological diseases and to restore sensory of motor functions of the body. Success stories have been written with the cochlear implant to restore hearing, with spinal cord stimulators to treat chronic pain as well as urge incontinence, and with deep brain stimulators in patients suffering from Parkinsons disease. Highly complex neural implants for novel medical applications can be miniaturized either by means of precision mechanics technologies using known and established materials for electrodes, cables, and hermetic packages or by applying microsystems technologies. Examples for both approaches will be introduced and discussed. Electrode arrays for recording of electrocorticograms during presurgical epilepsy diagnosis have been manufactured using approved materials and a marking laser to achieve an integration density that is adequate in the context of brain machine interfaces, e.g. on the motor cortex. Microtechnologies have to be used for further miniaturization to develop polymer-based flexible and light weighted electrode arrays to interface the peripheral and central nervous system. Polyimide as substrate and insulation material will be discussed as well as several application examples for nerve interfaces like cuffs, filament like electrodes and large arrays for subdural implantation.

Computational Tissue Volume Reconstruction of a Peripheral Nerve Using High-Resolution Light-Microscopy and Reconstruct

The development of neural cuff-electrodes requires several in vivo studies and revisions of the electrode design before the electrode is completely adapted to its target nerve. It is therefore favorable to simulate many of the steps involved in this process to reduce costs and animal testing. As the restoration of motor function is one of the most interesting applications of cuff-electrodes, the position and trajectories of myelinated fibers in the simulated nerve are important. In this paper, we investigate a method for building a precise neuroanatomical model of myelinated fibers in a peripheral nerve based on images obtained using high-resolution light microscopy. This anatomical model describes the first aim of our “Virtual workbench” project to establish a method for creating realistic neural simulation models based on image datasets. The imaging, processing, segmentation and technical limitations are described, and the steps involved in the transition into a simulation model are presented. The results showed that the position and trajectories of the myelinated axons were traced and virtualized using our technique, and small nerves could be reliably modeled based on of light microscopy images using low-cost OpenSource software and standard hardware. The anatomical model will be released to the scientific community.

Haemodynamic Responses to Selective Vagal Nerve Stimulation under Enalapril Medication in Rats

Selective vagal nerve stimulation (sVNS) has been demonstrated to lower blood pressure (BP) in rats without causing major side effects. This method might be adapted for the treatment of therapy-resistant hypertension in patients. Converting enzyme inhibitors (CEIs) are among the first drugs that are administered for arterial hypertension and prominently reduce BP primarily by interacting with the renin-angiotensin system of the kidneys. Beyond the reduction of BP, CEI have a positive effect on the survival rate after myocardial infarction; they reduce the rates of stroke and improve the neurohormonal status in heart-failure patients. If sVNS might be introduced as a therapy against resistant hypertension, patients will at least partially stay on their CEI medication. It is therefore the aim of this study to investigate the influence of the CEI enalapril on the haemodynamic and respiratory effects of sVNS. In 10 male Wistar rats, a polyimide-based multichannel-cuff-electrode was placed around the vagal nerve bundle to selectively stimulate the aortic depressor nerve fibres. Stimulation parameters were adapted to the thresholds of the individual animals and included repetition frequencies between 30 and 50 Hz, amplitudes of 0.5 to 1.5 mA and pulse widths between 0.4 ms and 1.0 ms. BP responses were detected with a microtip transducer in the left carotid artery, and electrocardiography was recorded with subcutaneous electrodes. After intravenous administration of enalapril (2 mg/kg bodyweight), the animals’ mean arterial blood pressures (MAPs) decreased significantly, while the heart rates (HRs) were not significantly influenced. The effects of sVNS on BP and HR were attenuated by enalapril but were still present. We conclude that sVNS can lower the MAP during enalapril treatment without relevant side effects.

Non-hermetic encapsulation for implantable electronic devices based on epoxy.

Hermetic and non-hermetic implant packaging are the two strategies to protect electronic systems from the humid conditions inside the human body. Within the scope of this work twelve different material combinations for a non-hermetic, high-reliable epoxy based encapsulation technique were characterized. Three EPO-TEK (ET) epoxies and one low budget epoxy were chosen for studies with respect to their processability, water vapor transmission rate (WVTR) and adhesion to two different ceramic-based substrates as well as to one standard FR4-substrate. Setups were built to analyze the mentioned properties for at least 30 days using an aging test in a moist environment. As secondary test subjects, commercially available USB flash drives (UFD) were successfully encapsulated inside the epoxies, soaked in phosphate buffered saline (PBS, pH=7.4), stored in an incubator (37°C) and tested for 256 days without failure. By means of epoxy WVTR (0.0278 g/day/m2) and degrease of adhesion (24.59 %) during 30 days in PBS, the combination of the standard FR4-substrate and the epoxy ET 301-2 was found to feature the best encapsulation properties. If a ceramic-based electronic system has to be used, the most promising combination consists of the alumina substrate and the epoxy ET 302-3M (WVTR: 0.0588 g/day/m2; adhesion drop: 49.58 %).

Implantable pulse oximetry on subcutaneous tissue.

Blood oxygen saturation is one of the most prominent measurement parameters in daily clinical routine. However up to now, it is not possible to continuously monitor this parameter reliably in mobile patients. High-risk patients suffering from cardiovascular diseases could benefit from long-term monitoring of blood oxygen saturation. In this paper, we present a minimally invasive, implantable patient monitor which is capable of monitoring vital signs. The capability of this multimodal sensor to subcutaneously determine blood pressure, pulse and ECG has been demonstrated earlier. This paper focuses on monitoring of blood oxygen saturation. Even though the signal amplitudes are much weaker than for standard extracorporeal measurements, photoplethysmographic signals were recorded with high quality in vivo directly on subcutaneous muscle tissue. For the first time, it has been shown that blood oxygen saturation can be measured with an implantable, but extravascular sensor. The sensor was implanted for two weeks in a sheep and did not cause any complications. This opens new perspectives for home monitoring of patients with cardiovascular diseases.

Epoxy casting used as nonhermetic encapsulation technique for implantable electronic devices

Implantable medical applications experienced a rapid growth since starting in the late 1950s with the first pacemakers. However, there are only two main packaging strategies available to protect the implanted electronics from the body environment. While hermetic packaging oftentimes seems to be more feasible, nonhermetic encapsulation can be an alternative under certain conditions. Previous studies using commercially available USB flash drives (UFD) pointed out the feasibility of using epoxy resins as encapsulant material. Based on this study, the water uptake was measured according to ISO 294-3 to determine the water diffusion rate of three EPO-TEK (ET) epoxies. The average water uptake Me for ET 301 was 3.18 %mass, for ET 301-2 it was 1.81 %mass and for ET 302-3M it was 2.34 %mass. The calculated diffusion constant D for ET 301 was 3.61E-13 m2/s, for ET 301-2 it was 3.63E-13 m2/s and for ET 302-3M it was found at 1.98E-13 m2/s. Next, we developed a setup in which eight microcontrollers were fully casted into two selected types of epoxies, four respectively. The casted microcontrollers where immersed in phosphate buffered saline (PBS, pH=7.4) and incubated at a temperature of 37 °C corresponding to the human body core temperature. The electronics were tested for 78 days without malfunctioning.

In-vivo characterization of a 0.8 – 3 µV RMS input-noise versatile CMOS pre-amplifier

The following work presents a CMOS-integrated low-noise pre-amplifier (LNA) for bio-potential recordings, which is part of a multi-channel neural recording system. The versatile pre-amplifier channel features a tunable lower cut-off frequency from 0.2 Hz to 10 kHz, an upper cut-off frequency from 37.9 Hz to 11 kHz, and a middle-band gain from 41 to 45 dB. With its variable power consumption from 3.3 μW to 1 mW, the input-referred noise can be set from 2 down to 0.8 μVRMS. The pre-amplifier, fabricated in a 0.35 μm CMOS process, was successfully tested for ECG, EMG, and EEG applications.