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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.

Background and purpose In patients treated with vagus nerve stimulation (VNS) for drug resistant epilepsy (DRE), up to a third of patients will eventually not respond to the therapy. As VNS therapy requires surgery for device implantation, prediction of response prior to surgery is desirable. It is hypothesized that neurophysiological investigations related to the mechanisms of action of VNS may help to differentiate VNS responders from non-responders prior to the initiation of therapy. Methods In a prospective series of DRE patients, polysomnography, heart rate variability (HRV) and cognitive event related potentials were recorded. Polysomnography and HRV were repeated after 1 year of treatment with VNS. Polysomnography, HRV and cognitive event related potentials were compared between VNS responders (>= 50% reduction in seizure frequency) and non-responders. Results Fifteen out of 30 patients became VNS responders after 1 year of VNS treatment. Prior to treatment with VNS, the amount of deep sleep (NREM 3), the HRV high frequency (HF) power and the P3b amplitude were significantly different in responders compared to non-responders (P = 0.007; P = 0.001; P = 0.03). Conclusion Three neurophysiological parameters, NREM 3, HRV HF and P3b amplitude, were found to be significantly different in DRE patients who became responders to VNS treatment prior to initiation of their treatment with VNS. These non-invasive recordings may be used as characteristics for response in future studies and help avoid unsuccessful implantations. Mechanistically these findings may be related to changes in brain regions involved in the so-called vagal afferent network.

Objective Patients diagnosed with Lennox Gastaut syndrome (LGS), an epileptic encephalopathy characterized by usually drug resistant generalized and focal seizures, are often considered as candidates for vagus nerve stimulation (VNS). Recent research shows that heart rate variability (HRV) differs in epilepsy patients and is related to VNS treatment response. This study investigated pre-ictal HRV in generalized onset seizures of patients with LGS in correlation with their VNS response. Methods In drug resistant epilepsy (DRE) patients diagnosed with LGS video-electroencephalography recording was performed during their pre-surgical evaluation. Six HRV parameters (time and-, frequency domain, non-linear parameters) were evaluated for every seizure in epochs of 10 min at baseline (60 to 50 min before seizure onset) and pre-ictally (10 min prior to seizure onset). The results were correlated to VNS response after one year of VNS therapy. Results Seven patients and 31 seizures were included, two patients were classified as VNS responders (≥ 50 % seizure reduction). No difference in pre-ictal HRV parameters between VNS responders and VNS non-responders could be found, but high frequency (HF) power, reflecting the parasympathetic tone increased significantly in the pre-ictal epoch in both VNS responders and VNS non-responders (p = 0.017, p = 0.004). Significance In this pilot data pre-ictal HRV did not differ in VNS responders compared to VNS non-responders, but showed a significant increase in HF power – a parasympathetic overdrive - in both VNS responders and VNS non-responders. This sudden autonomic imbalance might have an influence on the cardiovascular system in the ictal period. Generalized tonic-clonic seizures are regarded as the main risk factor for SUDEP and severe seizure-induced autonomic imbalance may play a role in the pathophysiological pathway.

Facilitation of object processing in the brain due to a related context (priming) can be influenced by both semantic connections and perceptual similarity. It is thus important to discern these two when evaluating the spatio-temporal dynamics of primed object processing. The repetition-priming paradigm frequently used to study perceptual priming is, however, unable to differentiate between the mentioned priming effects, possibly leading to confounded results. In the current study, we recorded brain signals from the scalp and cerebral convexity of nine patients with refractory epilepsy in response to related and unrelated image-pairs, all of which shared perceptual features while only related ones had a semantic connection. While previous studies employing a repetition-priming paradigm observed largely overlapping networks between semantic and perceptual priming effects, our results suggest that this overlap is only partial (both temporally and spatially). These findings stress the importance of controlling for perceptual features when studying semantic priming.

To what extent electrocorticography (ECoG) and electroencephalography (scalp EEG) differ in their capability to locate sources of deep brain activity is far from evident. Compared to EEG, the spatial resolution and signal-to-noise ratio of ECoG is superior but its spatial coverage is more restricted, as is arguably the volume of tissue activity effectively measured from. Moreover, scalp EEG studies are providing evidence of locating activity from deep sources such as the hippocampus using high-density setups during quiet wakefulness. To address this question, we recorded a multimodal dataset from 4 patients with refractory epilepsy during quiet wakefulness. This data comprises simultaneous scalp, subdural and depth EEG electrode recordings. The latter was located in the hippocampus or insula and provided us with our "ground truth" for source localization of deep activity. We applied independent component analysis (ICA) for the purpose of separating the independent sources in theta, alpha and beta frequency band activity. In all patients subdural- and scalp EEG components were observed which had a significant zero-lag correlation with one or more contacts of the depth electrodes. Subsequent dipole modeling of the correlating components revealed dipole locations that were significantly closer to the depth electrodes compared to the dipole location of non-correlating components. These findings support the idea that components found in both recording modalities originate from neural activity in close proximity to the depth electrodes. Sources localized with subdural electrodes were ~70% closer to the depth electrode than sources localized with EEG with an absolute improvement of around ~2cm. In our opinion, this is not a considerable improvement in source localization accuracy given that, for clinical purposes, ECoG electrodes were implanted in close proximity to the depth electrodes. Furthermore, the ECoG grid attenuates the scalp EEG, due to the electrically isolating silastic sheets in which the ECoG electrodes are embedded. Our results on dipole modeling show that the deep source localization accuracy of scalp EEG is comparable to that of ECoG. SIGNIFICANCE STATEMENT: Deep and subcortical regions play an important role in brain function. However, as joint recordings at multiple spatial scales to study brain function in humans are still scarce, it is still unresolved to what extent ECoG and EEG differ in their capability to locate sources of deep brain activity. To the best of our knowledge, this is the first study presenting a dataset of simultaneously recorded EEG, ECoG and depth electrodes in the hippocampus or insula, with a focus on non-epileptiform activity (quiet wakefulness). Furthermore, we are the first study to provide experimental findings on the comparison of source localization of deep cortical structures between invasive and non-invasive brain activity measured from the cortical surface. ispartof: NEUROIMAGE vol:223 ispartof: location:United States status: published

Suppressing irrelevant information in decision making is an essential everyday skill. We studied whether this ability could be improved in epileptic patients during vagus nerve stimulation (VNS). VNS is known to increase norepinephrine (NE) in the brain. NE is thought to improve several aspects of cognitive control, including the suppression of irrelevant information. Nineteen epileptic VNS patients executed the Eriksen flanker task twice, both during on and off stimulation. Distractor interference was indexed by the congruency effect, a standard empirical marker of cognitive control. We found a reduced congruency effect during stimulation, which indicates an improved ability to suppress distractor interference. This effect was only found in patients that are clinically determined VNS-responders (n = 10). As VNS increases NE in VNS-responders, our finding suggests a beneficial role of NE in cognitive control. At the same time, it suggests that VNS does not only reduce seizure frequency in epileptic patients, but also improves cognitive control.

BACKGROUND: Depression is the most common psychiatric comorbidity in epilepsy patients. The lack of success with current pharmacological interventions for this patient population, highlights the importance of optimizing non-pharmacological neuromodulatory treatments such as vagus nerve stimulation (VNS). Studies on the antidepressant effect of VNS in epilepsy patients may be confounded by concurrent anti-epileptic drug therapy. To date, studies in epilepsy models overcoming this problem are lacking. OBJECTIVE: We investigated whether VNS affects anhedonia, a key symptom of major depression, in the kainic acid rat model for temporal lobe epilepsy. METHODS: Anhedonia was assessed in kainic acid (KA) and saline (SAL) injected rats using the saccharin preference test (SPT). To exclude differences in taste perception, the quinine aversion test (QAT) was performed. Both groups were randomly subdivided in a VNS and a SHAM group, yielding 4 experimental arms: KA-VNS, KA-SHAM, SAL-VNS and SAL-SHAM. Both VNS groups received 2 weeks of VNS, while the SHAM groups were not stimulated. Thereafter, the SPT and QAT were repeated. RESULTS: Saccharin preference was significantly reduced in the KA compared to the SAL rats (P < 0.05), without differences in quinine aversion. Two weeks of VNS significantly increased the saccharin preference in the KA-VNS group (P < 0.05), while it had no effect on quinine aversion. No effects of VNS or SHAM were found in the other groups. CONCLUSION: The KA rats displayed anhedonia which was significantly decreased by VNS, indicating that this neuromodulatory treatment could likewise diminish depressive symptoms in patients suffering from temporal lobe epilepsy and comorbid depression.

SUMMARY Purpose: Despite different treatment options for patients with refractory epilepsy such as epilepsy surgery and neurostimulation, many patients still have seizures and/or drug-related cerebral and systemic side effects. Local intracerebral delivery of antiepileptic compounds may represent a novel strategy with specific advantages such as the option of higher local doses and reduced side effects. In this study we evaluate the antiepileptic effect of local delivery of adenosine in the kainic acid rat model, a validated model for temporal lobe epilepsy. Methods: Fifteen rats, in which intraperitoneal kainic acid injection had induced spontaneous seizures, were implanted with a combination of depth electrodes and a cannula in both hippocampi. Cannulas were connected to osmotic minipumps to allow continuous hippocampal delivery. Rats were freely moving and permanently monitored by video-EEG (electroencephalography). Seizures were scored during 2 weeks of local hippocampal delivery of saline (baseline), followed by 2 weeks of local adenosine (6 mg/ml) (n = 10) or saline (n = 5) delivery (0.23 ll/h) (treatment). In 7 of 10 adenosine-treated rats, saline was also delivered during a washout period. Results: During the treatment period a mean daily seizure frequency reduction of 33% compared to the baseline rate was found in adenosine-treated rats (p < 0.01). Four rats had a seizure frequency reduction of at least 50%. Both nonconvulsive and convulsive seizures significantly decreased during the treatment period. In the saline-control group, mean daily seizure frequency increased with 35% during the treatment period. Conclusions: This study demonstrates the antiseizure effect of continuous adenosine delivery in the hippocampi in rats with spontaneous seizures.

It has been shown that vagus nerve stimulation (VNS) has an antidepressant-like effect in the forced swim test. The mechanism of action underlying this effect is incompletely understood, but there is evidence suggesting that the locus coeruleus (LC) may play an important role. In this study, noradrenergic LC neurons were selectively lesioned to test their involvement in the antidepressant-like effect of VNS in the forced swim test. Forced swim test behavior was assessed in rats that were subjected to VNS or sham treatment. In half of the VNS-treated animals, the noradrenergic neurons from the LC were lesioned using the selective neurotoxin DSP-4 [ N -(2-chloroethyl)- N -ethyl-2-bromobenzylamine hydrochloride], yielding three experimental arms: sham, VNS and DSP-4-VNS (n = 8 per group). Furthermore, the open field test was performed to evaluate locomotor activity. A dopamine-β-hydroxylase immunostaining was performed to confirm lesioning of noradrenergic LC neurons. VNS significantly reduced the percentage of immobility time in the forced swim test compared to sham treatment (median: 56%, interquartile range: 41% vs. median: 75%, interquartile range: 12%). This antidepressant-like effect of VNS could not be demonstrated in the DSP-4-VNS group (median: 79%, interquartile range: 33%). Locomotor activity in the open field test was not different between the three treatment arms. The absence of hippocampal dopamine-β-hydroxylase immunostaining in the DSP-4-treated rats confirmed the lesioning of noradrenergic neurons originating from the brainstem LC. The results of this study demonstrate that the noradrenergic neurons from the LC play an important role in the antidepressant-like effect of VNS.

Contains fulltext : 160981.pdf (Publisher’s version ) (Closed access) 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 (=

In this study, we present long-term results from patients with medial temporal lobe (MTL) epilepsy treated with deep brain stimulation (DBS). Since 2001, 11 patients (8M) with refractory MTL epilepsy underwent MTL DBS. When unilateral DBS failed to decrease seizures by > 90%, a switch to bilateral MTL DBS was proposed. After a mean follow-up of 8.5 years (range: 67–120 months), 6/11 patients had a ≥ 90% seizure frequency reduction with 3/6 seizure-free for > 3 years; three patients had a 40%–70% reduction and two had a < 30% reduction. In 3/5 patients switching to bilateral DBS further improved outcome. Uni- or bilateral MTL DBS did not affect neuropsychological functioning. This open study with an extended long-term follow-up demonstrates maintained efficacy of DBS for MTL epilepsy. In more than half of the patients, a seizure frequency reduction of at least 90% was reached. Bilateral MTL DBS may herald superior efficacy in unilateral MTL epilepsy.

Objective The effects of Deep Brain Stimulation (DBS) have been studied primarily by electrophysiological and neurochemical studies, which lack the ability to elucidate DBS-related responses on a whole-brain scale. With this study our aim is to investigate DBS-induced global neuronal network activation in rats with functional Magnetic Resonance Imaging (fMRI). Methods Three times FMRI was done in seven rats, which were stereotactically implanted with a MR-compatible DBS-electrode in the right hippocampus. High frequency Poisson distributed stimulation was applied using a block-design paradigm. Response maps ( p Results Our data indicate that real-time hippocampal DBS evokes a uni- or bilateral BOLD response in hippocampal and mesolimbic structures, depending on the applied stimulation intensity. Results were reproducible in time and in-between subjects. Conclusions We present that DBS-fMRI can be used to detect whole-brain responses to circuit activation with different stimulation intensities, making this technique potentially powerful for exploring DBS-induced cerebral changes for preclinical and clinical DBS. Key message A better understanding of the whole-brain effect of DBS is necessary to improve treatment efficacy in patients. Successful translation of this research to patients might reduce the number of non-responders to this invasive and expensive treatment.

The cytoplasmic Ca2+ concentration ([Ca2+]i) is an important factor determining the functional state of blood-brain barrier (BBB) endothelial cells but little is known on the effect of dynamic [Ca2+]i changes on BBB function. We applied different agonists that trigger [Ca2+]i oscillations and determined the involvement of connexin channels and subsequent effects on endothelial permeability in immortalized and primary brain endothelial cells. The inflammatory peptide bradykinin (BK) triggered [Ca2+]i oscillations and increased endothelial permeability. The latter was prevented by buffering [Ca2+]i with BAPTA, indicating that [Ca2+]i oscillations are crucial in the permeability changes. Bradykinin-triggered [Ca2+]i oscillations were inhibited by interfering with connexin channels, making use of carbenoxolone, Gap27, a peptide blocker of connexin channels, and Cx37/43 knockdown. Gap27 inhibition of the oscillations was rapid (within minutes) and work with connexin hemichannel-permeable dyes indicated hemichannel opening and purinergic signaling in response to stimulation with BK. Moreover, Gap27 inhibited the BK-triggered endothelial permeability increase in in vitro and in vivo experiments. By contrast, [Ca2+]i oscillations provoked by exposure to adenosine 5’ triphosphate (ATP) were not affected by carbenoxolone or Gap27 and ATP did not disturb endothelial permeability. We conclude that interfering with endothelial connexin hemichannels is a novel approach to limiting BBB-permeability alterations.

The mechanism of action of vagus nerve stimulation (VNS) for pharmacoresistant epilepsy is unknown and the therapeutic outcome is highly variable. We investigated stimulation-induced vagus nerve electrophysiological responses in rats using various stimulation parameters. Conduction velocity, I 50, rheobase and chronaxie were calculated. We identified an early and late component corresponding to an afferent compound action potential (CAP) and a remote laryngeal motor-evoked potential (LMEP), respectively. The conduction velocity (CAP: 26.2 ± 1.4 m/s; LMEP: 32.4 ± 2.4 m/s) and I 50 (CAP: 2.4 ± 0.3 mA; LMEP: 1.8±0.2 mA) were significantly different for both components, the rheobase (CAP: 140±30 μA; LMEP: 110±26 μA) and chronaxie (CAP: 66±7 μs; LMEP: 73±9 μs) were not. Using a pulse of 10 μs, the CAP saturated between 4–5 mA. Our method can be used to record VNS-induced electrophysiological responses in rats and provides an objective biomarker for electrical stimulation with various parameters in an experimental set-up. Our findings are potentially useful for clinical purposes in the sense that combination of VNS and recording of vagal nerve CAPs may help clinicians to determine the individual optimal intensity required to fully activate fast-conducting afferent fibers.