The potential of invasive and non-invasive vagus nerve stimulation to improve verbal memory performance in epilepsy patients.

It has been demonstrated that acute vagus nerve stimulation (VNS) improves word recognition memory in epilepsy patients. Transcutaneous auricular vagus nerve stimulation (taVNS) has gained interest as a non-invasive alternative to improve cognition. In this prospective randomized cross-over study, we investigated the effect of both invasive VNS and taVNS on verbal memory performance in 15 patients with drug-resistant epilepsy. All patients conducted a word recognition memory paradigm in 3 conditions: VNS ON, VNS OFF and taVNS (3-period 3-treatment cross-over study design). For each condition, patients memorized 21 highlighted words from text paragraphs. Afterwards, the intervention was delivered for 30 s. Immediate recall and delayed recognition scores were obtained for each condition. This memory paradigm was repeated after 6 weeks of VNS therapy in 2 conditions: VNS ON and VNS OFF (2-period 2-treatment cross-over study design). Acute VNS and taVNS did not improve verbal memory performance. Immediate recall and delayed recognition scores were significantly improved after 6 weeks of VNS treatment irrespective of the acute intervention. We can conclude that the previously described positive effects of invasive VNS on verbal memory performance could not be replicated with invasive VNS and taVNS. An improved verbal memory performance was seen after 6 weeks of VNS treatment, suggesting that longer and more repetitive stimulation of the vagal pathway is required to modulate verbal memory performance.Clinical trial registration number: NCT05031208.

Laryngeal Muscle-Evoked Potential Recording as an Indicator of Vagal Nerve Fiber Activation.

BACKGROUND: Vagus nerve stimulation (VNS) is an adjunctive therapy for drug-resistant epilepsy. Noninvasive evoked potential recordings in laryngeal muscles (LMEPs) innervated by vagal branches may provide a marker to assess effective vagal nerve fiber activation. We investigated VNS-induced LMEPs in patients with epilepsy in acute and chronic settings. MATERIALS AND METHODS: A total of 17 of 25 patients underwent LMEP recordings at initiation of therapy (acute group); 15 of 25 patients after one year of VNS (chronic group); and 7 of 25 patients were tested at both time points (acute + chronic group). VNS-induced LMEPs were recorded following different pulse widths and output currents using six surface laryngeal EMG electrodes to calculate input/output curves and estimate LMEP latency, threshold current for minimal (Ithreshold), half-maximal (I50), and 95% of maximal (I95) response induction and amplitude of maximal response (Vmax). These were compared with the acute + chronic group and between responders and nonresponders in the acute and chronic group. RESULTS: VNS-induced LMEPs were present in all patients. Ithreshold and I95 values ranged from 0.25 to 1.00 mA and from 0.42 to 1.77 mA, respectively. Estimated mean LMEP latencies were 10 ± 0.1 milliseconds. No significant differences between responders and nonresponders were observed. In the acute + chronic group, Ithreshold values remained stable over time. However, at the individual level in this group, Vmax was lower in all patients after one year compared with baseline. CONCLUSIONS: Noninvasive VNS-induced LMEP recording is feasible both at initiation of VNS therapy and after one year. Low output currents (0.25-1.00 mA) may be sufficient to activate vagal Aα-motor fibers. Maximal LMEP amplitudes seemed to decrease after chronic VNS therapy in patients.

Transcutaneous auricular vagus nerve stimulation cannot modulate the P3b event-related potential in healthy volunteers.

OBJECTIVE: The release of cortical norepinephrine is one of the possible mechanisms of action of vagus nerve stimulation (VNS), a neuromodulatory treatment currently under investigation for cognitive impairment. Transcutaneous auricular VNS (taVNS) may be able to activate vagal nerve branches ending in the brainstem's locus coeruleus (LC) non-invasively. The aim was to investigate if acute taVNS can modulate the P3b, a cognitive event-related potential (ERP) reflecting noradrenergic brain activation under control of the LC. METHODS: Thirty-nine healthy volunteers performed an auditory oddball task during no stimulation, sham stimulation and taVNS in a randomized order. P3b amplitude, latency and behavioral outcome parameters were compared between conditions using linear mixed models. RESULTS: P3b amplitude and latency during taVNS did not differ significantly from sham or control. Reaction time shortened and P3b latency prolonged with repetition of the oddball task. CONCLUSIONS: We were unable to modulate cognitive ERPs by means of acute taVNS in a large group of healthy volunteers. SIGNIFICANCE: Targeting vagal nerve fibres via a transcutaneous approach did not alter the P3b in healthy participants. The stimulation parameters used and transient delivery of taVNS might be insufficient to adequately modulate the LC. Also, a disbalanced locus coeruleus - norepinephrine system in patients may be more prone for improvement.

Pre-ictal heart rate variability alterations in focal onset seizures and response to vagus nerve stimulation.

PURPOSE: Vagus nerve stimulation (VNS) is an effective and well-known treatment for drug resistant epilepsy (DRE) patients since 1997, yet prediction of treatment response before implantation is subject of ongoing research. Neuroimaging and neurophysiological studies investigating the vagal afferent network in resting state documented that differences in between epilepsy patients were related to treatment response. This study investigated whether an event-related parameter, pre-ictal heart rate variability (HRV) is associated with response to VNS therapy. METHODS: DRE patients underwent video-electroencephalography (EEG) recording before VNS implantation. HRV parameters (time, non-linear and frequency domain) were assessed for every seizure during two 10 min timeframes: baseline (60 min before seizure onset) and pre-ictal (10 min before seizure onset). Pre-ictal HRV parameter alterations were correlated with VNS response after one year of VNS therapy and seizure characteristics (temporal/extratemporal, left/right or bilateral). RESULTS: 104 seizures from 22 patients were evaluated. Eleven patients were VNS responders with a seizure frequency reduction of ≥ 50 % after one year of VNS. In VNS responders no changes in HRV parameters were found while in VNS non-responders the time domain and non-linear HRV variables decreased significantly (p = 0.024, p = 0.005, p = 0.005) during the pre-ictal time frame. 10/11 VNS non-responders had a seizure lateralization to the left compared to 4/11 VNS responders. CONCLUSION: VNS non-responders were characterized by a significant decrease of pre-ictal HRV (time domain/non-linear variables) suggesting a sudden autonomic imbalance probably due to an impaired central autonomic function that makes it at the same time unlikely to respond to VNS.

Transcutaneous Vagus Nerve Stimulation Does Not Affect Verbal Memory Performance in Healthy Volunteers.

INTRODUCTION: Invasive vagus nerve stimulation (VNS) improves word recognition memory in patients with epilepsy. Recent studies with transcutaneous VNS (tVNS) have also shown positive effects on various subdomains of cognitive functioning in healthy volunteers. In this randomized, controlled, crossover study, we investigated the effect of tVNS on a word recognition memory paradigm in healthy volunteers to further investigate the potential of tVNS in the treatment of cognitive disorders. METHODS: We included 41 healthy participants aged between 18 and 30 years (young age group) and 24 healthy participants aged between 45 and 80 years (older age group). Each participant completed a word recognition memory paradigm during three different conditions: true tVNS, sham, and control. During true tVNS, stimulation was delivered at the cymba conchae. Sham stimulation was delivered by stimulating the earlobe. In the control condition, no stimulation was given. In each condition, participants were asked to remember highlighted words from three test paragraphs. Accuracy scores were calculated for immediate recall after each test paragraph and for delayed recognition at the end of the paradigm. We hypothesized that highlighted words from paragraphs in the true tVNS condition would be more accurately recalled and/or recognized compared to highlighted words from paragraphs in the sham or control condition. RESULTS: In this randomized study, tVNS did not affect the accuracy scores for immediate recall or delayed recognition in both age groups. The younger group showed significantly higher accuracy scores than the older group. The accuracy scores improved over time, and the most recently learned words were better recognized. Participants rated true tVNS as significantly more painful; however, pain was not found to affect accuracy scores. CONCLUSION: In this study, tVNS did not affect verbal memory performance in healthy volunteers. Our results could not replicate the positive effects of invasive VNS on word recognition memory in epilepsy patients. Future research with the aim of improving cognitive function should focus on the rational identification of optimized and individualized stimulation settings primarily in patients with cognitive deficits.

Recent advances in devices for vagus nerve stimulation.

INTRODUCTION: Vagus nerve stimulation (VNS) has become a valuable treatment option for refractory epilepsy and depression. To improve clinical efficacy and minimize side effects, novel device technology for VNS is under development and investigation. AREAS COVERED: For epilepsy, the AspireSR®, and SenTiva™ VNS therapy systems are the two most recently developed VNS devices. These novel devices have implemented a closed-loop approach and contain a cardiac based seizure detection algorithm. The mechanism of action of VNS remains to be further elucidated, but as preclinical research reveals VNS induced effects on brain plasticity, the autonomic nervous system and the inflammatory response, the indications of VNS are expanding. VNS devices are currently being investigated for stroke rehabilitation, treatment of chronic heart failure and rheumatoid arthritis. Recently devices to noninvasively affect vagus nerve functioning have been developed, with the aim of achieving similar effects without the drawbacks of a surgical procedure and continuous stimulation. EXPERT COMMENTARY: Several animal and human trials have shown promising results with minimal adverse events. However, further research needs to be conducted to validate the use of these devices and decide on optimal stimulation parameters.

EEG source connectivity to localize the seizure onset zone in patients with drug resistant epilepsy.

Electrical source imaging (ESI) from interictal scalp EEG is increasingly validated and used as a valuable tool in the presurgical evaluation of epilepsy as a reflection of the irritative zone. ESI of ictal scalp EEG to localize the seizure onset zone (SOZ) remains challenging. We investigated the value of an approach for ictal imaging using ESI and functional connectivity analysis (FC). Ictal scalp EEG from 111 seizures in 27 patients who had Engel class I outcome at least 1 year following resective surgery was analyzed. For every seizure, an artifact-free epoch close to the seizure onset was selected and ESI using LORETA was applied. In addition, the reconstructed sources underwent FC using the spectrum-weighted Adaptive Directed Transfer Function. This resulted in the estimation of the SOZ in two ways: (i) the source with maximal power after ESI, (ii) the source with the strongest outgoing connections after combined ESI and FC. Next, we calculated the distance between the estimated SOZ and the border of the resected zone (RZ) for both approaches and called this the localization error ((i) LEpow and (ii) LEconn respectively). By comparing LEpow and LEconn, we assessed the added value of FC. The source with maximal power after ESI was inside the RZ (LEpow = 0 mm) in 31% of the seizures and estimated within 10 mm from the border of the RZ (LEpow ≤ 10 mm) in 42%. Using ESI and FC, these numbers increased to 72% for LEconn = 0 mm and 94% for LEconn ≤ 10 mm. FC provided a significant added value to ESI alone (p < 0.001). ESI combined with subsequent FC is able to localize the SOZ in a non-invasive way with high accuracy. Therefore it could be a valuable tool in the presurgical evaluation of epilepsy.

Automated long-term EEG analysis to localize the epileptogenic zone.

Objective: We investigated the performance of automatic spike detection and subsequent electroencephalogram (EEG) source imaging to localize the epileptogenic zone (EZ) from long-term EEG recorded during video-EEG monitoring. Methods: In 32 patients, spikes were automatically detected in the EEG and clustered according to their morphology. The two spike clusters with most single events in each patient were averaged and localized in the brain at the half-rising time and peak of the spike using EEG source imaging. On the basis of the distance from the sources to the resection and the known patient outcome after surgery, the performance of the automated EEG analysis to localize the EZ was quantified. Results: In 28 out of the 32 patients, the automatically detected spike clusters corresponded with the reported interictal findings. The median distance to the resection in patients with Engel class I outcome was 6.5 and 15 mm for spike cluster 1 and 27 and 26 mm for cluster 2, at the peak and the half-rising time of the spike, respectively. Spike occurrence (cluster 1 vs. cluster 2) and spike timing (peak vs. half-rising) significantly influenced the distance to the resection (p < 0.05). For patients with Engel class II, III, and IV outcomes, the median distance increased to 36 and 36 mm for cluster 1. Localizing spike cluster 1 at the peak resulted in a sensitivity of 70% and specificity of 100%, positive prediction value (PPV) of 100%, and negative predictive value (NPV) of 53%. Including the results of spike cluster 2 led to an increased sensitivity of 79% NPV of 55% and diagnostic OR of 11.4, while the specificity dropped to 75% and the PPV to 90%. Significance: We showed that automated analysis of long-term EEG recordings results in a high sensitivity and specificity to localize the epileptogenic focus.

EEG Derived Brain Activity Reflects Treatment Response from Vagus Nerve Stimulation in Patients with Epilepsy.

The mechanism of action of vagus nerve stimulation (VNS) is yet to be elucidated. To that end, the effects of VNS on the brain of epileptic patients were studied. Both when VNS was switched "On" and "Off", the brain activity of responders (R, seizure frequency reduction of over 50%) was compared to the brain activity of nonresponders (NR, seizure frequency reduction of less than 50%). Using EEG recordings, a significant increase in P300 amplitude for R and a significant decrease in P300 amplitude for NR were found. We found biomarkers for checking the efficacy of VNS with accuracy up to 94%. The results show that P300 features recorded in nonmidline electrodes are better P300 biomarkers for VNS efficacy than P300 features recorded in midline electrodes. Using source localization and connectivity analyses, the activity of the limbic system, insula and orbitofrontal cortex was found to be dependent on VNS switched "On" versus "Off" or patient group (R versus NR). The results suggest an important role for these areas in the mechanism of action of VNS, although a larger patient study should be done to confirm the findings.

The Role of Skull Modeling in EEG Source Imaging for Patients with Refractory Temporal Lobe Epilepsy.

We investigated the influence of different skull modeling approaches on EEG source imaging (ESI), using data of six patients with refractory temporal lobe epilepsy who later underwent successful epilepsy surgery. Four realistic head models with different skull compartments, based on finite difference methods, were constructed for each patient: (i) Three models had skulls with compact and spongy bone compartments as well as air-filled cavities, segmented from either computed tomography (CT), magnetic resonance imaging (MRI) or a CT-template and (ii) one model included a MRI-based skull with a single compact bone compartment. In all patients we performed ESI of single and averaged spikes marked in the clinical 27-channel EEG by the epileptologist. To analyze at which time point the dipole estimations were closer to the resected zone, ESI was performed at two time instants: the half-rising phase and peak of the spike. The estimated sources for each model were validated against the resected area, as indicated by the postoperative MRI. Our results showed that single spike analysis was highly influenced by the signal-to-noise ratio (SNR), yielding estimations with smaller distances to the resected volume at the peak of the spike. Although averaging reduced the SNR effects, it did not always result in dipole estimations lying closer to the resection. The proposed skull modeling approaches did not lead to significant differences in the localization of the irritative zone from clinical EEG data with low spatial sampling density. Furthermore, we showed that a simple skull model (MRI-based) resulted in similar accuracy in dipole estimation compared to more complex head models (based on CT- or CT-template). Therefore, all the considered head models can be used in the presurgical evaluation of patients with temporal lobe epilepsy to localize the irritative zone from low-density clinical EEG recordings.

Impact of Vagal Nerve Stimulation on Objective Vocal Quality, a Pilot Study.

OBJECTIVE: The purpose of this study was to determine the impact of vagal nerve stimulation (VNS) on the vocal quality using the dysphonia severity index (DSI). It was hypothesized that the objective vocal quality and other vocal characteristics are disordered in comparison with an age- and gender-matched control group. In addition, the acoustic vocal parameters were compared during three conditions: at rest, during normal stimulation, and raised stimulation. A significant relation between the amount of stimulation and the presence of disturbed acoustic parameters was hypothesized. METHODS: Subjective (auditory-perceptual evaluation and voice handicap index) and objective (aerodynamic, vocal range, acoustic measurements and determination of the DSI) measurements were used to determine the vocal quality in 13 subjects with VNS in three different conditions (at rest and during normal and raised stimulation) and the age- and gender-matched control group. RESULTS: The subjects with VNS had a disordered perceptual vocal quality mainly characterized by the presence of a moderate roughness and slight breathiness, and the objective vocal quality by means of the DSI value is -2.4. During stimulation and especially during raised stimulation, the fundamental frequency is significantly increased. However, the subjects experienced no psychosocial handicapping effect of the vocal quality on the quality of life. CONCLUSIONS: Subjects with VNS have typical vocal characteristics. Ear, nose, and throat specialists and voice therapist must be aware of the presence of this vocal pattern at rest and during normal and raised stimulation. Especially, professional voice users and elite vocal performers must be informed before implantation.

Soft, comfortable polymer dry electrodes for high quality ECG and EEG recording.

Conventional gel electrodes are widely used for biopotential measurements, despite important drawbacks such as skin irritation, long set-up time and uncomfortable removal. Recently introduced dry electrodes with rigid metal pins overcome most of these problems; however, their rigidity causes discomfort and pain. This paper presents dry electrodes offering high user comfort, since they are fabricated from EPDM rubber containing various additives for optimum conductivity, flexibility and ease of fabrication. The electrode impedance is measured on phantoms and human skin. After optimization of the polymer composition, the skin-electrode impedance is only ~10 times larger than that of gel electrodes. Therefore, these electrodes are directly capable of recording strong biopotential signals such as ECG while for low-amplitude signals such as EEG, the electrodes need to be coupled with an active circuit. EEG recordings using active polymer electrodes connected to a clinical EEG system show very promising results: alpha waves can be clearly observed when subjects close their eyes, and correlation and coherence analyses reveal high similarity between dry and gel electrode signals. Moreover, all subjects reported that our polymer electrodes did not cause discomfort. Hence, the polymer-based dry electrodes are promising alternatives to either rigid dry electrodes or conventional gel electrodes.

The P3 event-related potential is a biomarker for the efficacy of vagus nerve stimulation in patients with epilepsy.

Currently, the mechanism of action of vagus nerve stimulation (VNS) is not fully understood, and it is unclear which factors determine a patient's response to treatment. Recent preclinical experiments indicate that activation of the locus coeruleus noradrenergic system is critical for the antiepileptic effect of VNS. This study aims to evaluate the effect of VNS on noradrenergic signaling in the human brain through a noninvasive marker of locus coeruleus noradrenergic activity: the P3 component of the event-related potential. We investigated whether VNS differentially modulates the P3 component in VNS responders versus VNS nonresponders. For this purpose, we recruited 20 patients with refractory epilepsy who had been treated with VNS for at least 18 months. Patients were divided into 2 groups with regard to their reduction in mean monthly seizure frequency: 10 responders (>50 %) and 10 nonresponders (≤50 %). Two stimulation conditions were compared: VNS OFF and VNS ON. In each condition, the P3 component was measured during an auditory oddball paradigm. VNS induced a significant increase of the P3 amplitude at the parietal midline electrode, in VNS responders only. In addition, logistic regression analysis showed that the increase of P3 amplitude can be used as a noninvasive indicator for VNS responders. These results support the hypothesis that activation of the locus coeruleus noradrenergic system is associated with the antiepileptic effect of VNS. Modulation of the P3 amplitude should be further investigated as a noninvasive biomarker for the therapeutic efficacy of VNS in patients with refractory epilepsy.