Recording of spontaneous vagus nerve activity during Pentylenetetrazol-induced seizures in rats.

BACKGROUND: Vagus nerve stimulation is a treatment for refractory epilepsy. The vagus nerve carries parasympathetic information and innervates multiple organs. As seizures are commonly associated with autonomic manifestations, we believe that biomarkers for diseases affecting autonomic functions such as epilepsy can be found in vagus nerve signals. NEW METHOD: We present a method to record vagus nerve electroneurogram (VENG) and detect in the VENG single unit activity in anesthetized rats during Pentylenetetrazol induced seizures using a true tripolar cuff electrode. RESULTS: The VENG consisted of high amplitude bursts and lower amplitude bursts synchronous to respiration and heartbeat respectively. The average spikes exhibited a triphasic shape with duration below 1.5ms and root mean square amplitude varied between 5.5 +/- 0.2 µV and 11.4 +/- 3.1 µV depending on the type of recording. An increase of the contact distance resulted in a signal amplitude increase. Application of Lidocaine led to a total disappearance of the recorded spontaneous spiking of the nerve. COMPARISON WITH EXISTING METHODS: True tripolar cuff electrodes exhibited a better performance in terms of artefact rejection, stability and reproducibility of the signal compared to commonly used hook electrodes which is of special interest in seizures where important motion and EMG artifacts are expected. CONCLUSION: We present a new method to record single unit activity of the vagus nerve during acute chemically induced seizures in rats and verified the neural origin of the recorded signals. This recording method might be a powerful tool to develop seizure biomarkers based on VENG.

An Intraneural Electrode for Bioelectronic Medicines for Treatment of Hypertension.

OBJECTIVES: 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 patient's 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. MATERIALS AND METHODS: Experiments were performed on six anesthetized pigs from which the BP was recorded using arterial catheters and the respiratory cycles by recording the airway pressure. An electrode comprising four tripolar channels was inserted longitudinally in the LVN of the animals to extract BP and respiration markers from the LVN and for selective LVNS. RESULTS: BP-related and respiratory-related neural profiles (BPnPs and RnPs, respectively) were derived from at least two electrode channels in all pigs. The BPnPs accurately resembled the BP waves and the RnPs accurately resembled the respiratory cycles, which suggests that those profiles could serve as BP and respiration markers, respectively. The BP was decreased by intraneural LVNS in all pigs and in four of those pigs such an effect was induced without major cardiac changes through a channel-selective stimulation. CONCLUSION: This study shows that it is feasible to extract BP and respiratory markers from the LVN with the tested intraneural electrode and suggests that this electrode could also be used for selective LVNS.

A Respiratory Marker Derived From Left Vagus Nerve Signals Recorded With Implantable Cuff Electrodes.

OBJECTIVE: 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. MATERIALS AND METHODS: The experiments were performed in 14 anesthetized pigs. Five pigs were subjected to changes of the respiratory frequency and nine to changes of the respiratory volume. The LVN electroneurogram (VENG) was recorded using two cuff electrodes and the respiratory cycles (RC) using a pressure transducer. To separate the afferent and efferent VENGs, vagotomy was performed between the cuffs in the first group of pigs. The VENG was squared to derive respiration-related neural profiles (RnPs) and their correlation with the RCs was investigated in regard to timing and magnitude parameters derived from the two waveforms. RESULTS: The RnPs were morphologically similar with the RCs and the average RnPs represented accurate copies of the average RCs. Consequently, the lung inflation/deflation RC and RnP components had the same duration, the respiratory frequency changes affected in the same way both waveforms and the RnP amplitude increased linearly with the lung inflation in all tested pigs (R2 values between 0.85 and 0.99). CONCLUSIONS: The RnPs comprise information regarding the timing and magnitude of the respiratory parameters. As those LVN profiles were derived using implantable means, this study indicates that the RnPs could serve as respiratory markers in implantable systems.

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.

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.

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 S=0.98-0.99 for all stimulation configurations, while recording selectivity configurations was in the range of S=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.

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 (S = 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.

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.