Thomas Nørgaard Nielsen

Transverse Versus Longitudinal Tripolar Configuration for Selective Stimulation With Multipolar Cuff Electrodes

The ability to stimulate subareas of a nerve selectively is highly desirable, since it has the potential of simplifying surgery to implanting one cuff on a large nerve instead of many cuffs on smaller nerves or muscles, or alternatively can improve function where surgical access to the smaller nerves is limited. In this paper, stimulation was performed with a four-channel multipolar cuff electrode implanted on the sciatic nerve of nine rabbits to compare the extensively researched longitudinal tripolar configuration with the transverse tripolar configuration, which has received less interest. The performance of these configurations was evaluated in terms of selectivity in recruitment of the three branches of the sciatic nerve. The results showed that the transverse configuration was able to selectively activate the sciatic nerve branches to a functionally relevant level in more cases than the longitudinal configuration (20/27 versus 11/27 branches) and overall achieved a higher mean selectivity [0.79 ± 0.13 versus 0.61 ± 0.09 (mean ± standard deviation)]. The transverse configuration was most successful at recruiting the small cutaneous and medium-sized peroneal branches, and less successful at recruiting the large tibial nerve.

Fascicle-Selectivity of an Intraneural Stimulation Electrode in the Rabbit Sciatic Nerve

The current literature contains extensive research on peripheral nerve interfaces, including both extraneural and intrafascicular electrodes. Interfascicular electrodes, which are in-between these two with respect to nerve fiber proximity have, however, received little interest. In this proof-of-concept study, an interfascicular electrode was designed to be implanted in the sciatic nerve and activate the tibial and peroneal nerves selectively of each other, and it was tested in acute experiments on nine anaesthetized rabbits. The electrode was inserted without difficulty between the fascicles using blunt glass tools, which could easily penetrate the epineurium but not the perineurium. Selective activation of all tibial and peroneal nerves in the nine animals was achieved with high selectivity (Ŝ = 0.98 ± 0.02). Interfascicular electrodes could provide an interesting addition to the bulk of peripheral nerve interfaces available for neural prosthetic devices. Since interfascicular electrodes can be inserted without fully freeing the nerve and have the advantage of not confining the nerve to a limited space, they could, e.g., be an alternative to extraneural electrodes in locations where such surgery is complicated due to blood vessels or fatty tissue. Further studies are, however, necessary to develop biocompatible electrodes and test their stability and safety in chronic experiments.

Comparison of Mono-, Bi-, and Tripolar Configurations for Stimulation and Recording With an Interfascicular Interface

Previous studies have indicated that electrodes placed between fascicles can provide nerve recruitment with high topological selectivity if the areas of interest in the nerve are separated with passive elements. In this study, we investigated if this separation of fascicles also can provide topologically selective nerve recordings and compared the performance of mono-, bi-, and tripolar configurations for stimulation and recording with an intra-neural interface. The interface was implanted in the sciatic nerve of 10 rabbits and achieved a median selectivity of Ŝ=0.98-0.99 for all stimulation configurations, while recording selectivity configurations was in the range of Ŝ=0.70-0.80 with the monopolar configuration providing the lowest and the average reference configuration the highest recording selectivity. Interfascicular electrodes could provide an interesting addition to the bulk of peripheral nerve interfaces available for neural prosthetic devices. The separation of the nerve into chambers by the passive elements of the electrode could ensure a higher selectivity than comparable cuff electrodes and the intra-neural location could provide an option of targeting mainly central fascicles. Further studies are, however, still required to develop biocompatible electrodes and test their stability and safety in chronic experiments.

A respiratory marker derived from left vagus nerve signals recorded with implantable cuff electrodes

Left vagus nerve (LVN) stimulation (LVNS) has been tested for lowering the blood pressure (BP) in patients with resistant hypertension (RH). Whereas, closed‐loop LVNS (CL‐LVNS) driven by a BP marker may be superior to open‐loop LVNS, there are situations (e.g., exercising) when hypertension is normal. Therefore, an ideal anti‐RH CL‐LVNS system requires a variable to avoid stimulation in such conditions, for example, a respiratory marker ideally extracted from the LVN. As the LVN conducts respiratory signals, this study aimed to investigate if such signals can be recorded using implantable means and if a marker to monitor respiration could be derived from such recordings.

A Blood Pressure-Related Profile Extracted from Pig Left Vagus Nerves Using Cuff Electrodes

Vagus nerve (VN) stimulation (VNS) is used in epilepsy and tested for blood pressure (BP) control. Whereas the present VNS methods are scheduled, closed-loop VNS (CL-VNS) may be safer and more efficient. However, CL-VNS for epilepsy and BP control require implantable means to monitor seizures and BP changes and such means are not available yet. It is known that the VN conducts afferent BP-related signals, and that seizures are often preceded by BP changes. This study was performed to investigate if such BP-related signals can be recorded using implantable means and if information regarding BP changes can be derived from such recordings. The experiments were performed in two pigs subjected to adrenaline administration for BP increase. The left VN electroneurogram (VENG) was recorded using cuff electrodes, the BP using carotid catheters and the ECG using surface electrodes. By ensemble averaging the VENG activity relative to the R-peaks, afferent BP-related VENG profiles (BP-VENGs) were extracted from the VENG. The BP-VENGs were morphologically similar, proportional and in phase with the carotid BP pulses. The maximum amplitude of those profiles was used to derive a phasic VENG component (pVENG) which changed proportional to the mean BP changes. It is concluded that the BP-VENGs and pVENG could eventually be implemented in CL-VNS for epilepsy and BP control to monitor BP changes and modulate on-demand VNS.

Early Detection of Epileptic Seizures in Pigs Based on Vagus Nerve Activity

Vagus nerve stimulation is currently used as a treatment of otherwise intractable epilepsy. The efficacy of the treatment does, however, remain modest, but could potentially be improved by on-demand stimulation. A method for early seizure detection in rats based on vagus nerve activity was described previously. Such methods could enable closed loop on-demand stimulation. In this study, we tested the method in three pigs. Early prediction of seizures, i.e. prior to the onset of tonic-clonic seizures, was possible in all animals, whereas administration of adrenaline did not provoke false detections.

A neural blood pressure marker for bioelectronic medicines for treatment of hypertension

A novel therapeutic approach for treating resistant hypertension could be the use of bioelectronic medicines to achieve blood pressure (BP) control in implanted patients by closed-loop stimulation of the left vagus nerve (LVN). However, such a technology would require an implantable BP marker, which is not available yet. As it is known that the LVN conducts afferent BP-related signals, this study aimed to investigate if such signals could be recorded with implantable means and used to derive BP markers. The present experiments were performed in anesthetized pigs subjected to a transient or stable BP increase induced by adrenaline administration. The LVN signals recorded with cuff electrodes and the BP waves recorded with carotid catheters were ensemble averaged relative to the R-peaks of the electrocardiogram. Through this procedure, afferent BP-related neural profiles (BPnPs) were derived from the LVN signals. As the BPnPs represented accurate copies of the BP waves, the timing parameters of both waveforms were almost the same and the BPnP amplitude increased linearly with the diastolic, systolic and mean BP. These results indicate that the BPnPs comprise accurate BP information and that the BPnP amplitude could serve as a BP marker in implantable systems.

An intraneural electrode for bioelectronic medicines for treatment of hypertension

As the left vagus nerve (LVN) mediates a baroreflex blood pressure (BP) decrease, LVN stimulation (LVNS) could be a therapy for hypertension. Moreover, LVNS could elegantly be adjusted to the patients actual BP and physical activity by using the neural information about BP and respiration extractable from LVN. However, unselective LVNS will trigger undesirable side‐effects and therefore we here investigated the feasibility of using an intraneural electrode for extracting BP and respiration markers from the LVN and for selective LVNS.

Stimulation Waveforms for the Selective Activation of Baroreceptor Nerve Fibers in the Cervical Vagus Nerve

The recruitment of large nerve fibers before small fibers is an issue in many neuromodulation applications. It may, e.g., cause the larynx to be activated by vagus nerve stimulation (VNS) at lower thresholds than required for activation of clinically relevant fibers, such as baroreceptors. We here present results from two animals, indicating that a custom waveform, combining known techniques, can activate the baroreflex with suppressed laryngeal activation, as compared to rectangular pulses. Such selective baroreflex activation with tolerable side-effects could potentially help advance VNS as a treatment modality in resistant hypertension.

Changes in vagus nerve activity associated with ictal tachycardia in pigs

OBJECTIVE Ictal tachycardia (IT) is common and may pave the way towards cardiac conditions with high risk potential. However, the mechanisms of IT remain obscure and therefore difficult to control. For example, whereas IT is associated with a sympathetic surge, it is unclear why the IT effects are not opposed by baroreflex cardiac inhibition during seizures. As the vagus nerves (VN) are main mediators for such baroreflexes, this study was performed to investigate the VN activity in IT. METHODS The present experiments were performed in ten pigs where IT seizures were induced by controlled infusion of pentylenetetrazole. The electrocorticogram was recorded using a cranial electrode, the electrocardiogram (ECG) using surface electrodes and the blood pressure (BP) using a catheter inserted in the right carotid artery. The VN activity was recorded from both nerves using cuff electrodes and further analyzed in correlation with the cortical seizures and the associated heart rate (HR), BP and HR variability (HRV) changes. RESULTS The cortical seizures progressed from spike-and-wave (SW) to tonic-clonic (TC) discharges associated with ECG, HR and BP changes proportional with this progression and comparable to the IT effects reported in humans. Those IT effects were accompanied by parasympathetic HRV changes, a 20% VN activation (p=0.004) before the onset of TC seizures, a suppression of this VN activation during the TC episode and a rebound VN activation by 79% (left VN, p=0.02) and 57% (right VN, p=0.03) after the TC offset. Further analysis of an afferent BP-related VN component and a mixed VN component showed normal BP-related afferent input and a suppressed efferent output through both nerves during the TC episode. CONCLUSIONS This study indicates a suppressed ictal VN activation and a rebound postictal VN activation, which may account for the absence of baroreflexes during seizures and the postictal cardiac inhibition, respectively.