Vagus nerve stimulation paired with tones restores auditory processing in a rat model of Rett syndrome

BackgroundRett syndrome is a rare neurological disorder associated with a mutation in the X-linked gene MECP2. This disorder mainly affects females, who typically have seemingly normal early development followed by a regression of acquired skills. The rodent Mecp2 model exhibits many of the classic neural abnormalities and behavioral deficits observed in individuals with Rett syndrome. Similar to individuals with Rett syndrome, both auditory discrimination ability and auditory cortical responses are impaired in heterozygous Mecp2 rats. The development of therapies that can enhance plasticity in auditory networks and improve auditory processing has the potential to impact the lives of individuals with Rett syndrome. Evidence suggests that precisely timed vagus nerve stimulation (VNS) paired with sound presentation can drive robust neuroplasticity in auditory networks and enhance the benefits of auditory therapy.ObjectiveThe aim of this study was to investigate the ability of VNS paired with tones to restore auditory processing in Mecp2 transgenic rats.MethodsSeventeen female heterozygous Mecp2 rats and 8 female wild-type (WT) littermates were used in this study. The rats were exposed to multiple tone frequencies paired with VNS 300 times per day for 20 days. Auditory cortex responses were then examined following VNS-tone pairing therapy or no therapy.ResultsOur results indicate that Mecp2 mutation alters auditory cortex responses to sounds compared to WT controls. VNS-tone pairing in Mecp2 rats improves the cortical response strength to both tones and speech sounds compared to untreated Mecp2 rats. Additionally, VNS-tone pairing increased the information contained in the neural response that can be used to discriminate between different consonant sounds.ConclusionThese results demonstrate that VNS-sound pairing may represent a strategy to enhance auditory function in individuals with Rett syndrome.     

The interaction of pulse width and current intensity on the extent of cortical plasticity evoked by vagus nerve stimulation

Background

Repeatedly pairing a tone with a brief burst of vagus nerve stimulation (VNS) results in a reorganization of primary auditory cortex (A1). The plasticity-enhancing and memory-enhancing effects of VNS follow an inverted-U response to stimulation intensity, in which moderate intensity currents yield greater effects than low or high intensity currents. It is not known how other stimulation parameters effect the plasticity-enhancing effects of VNS.

Late-onset periodic asystolia during vagus nerve stimulation

Cardiac changes may occasionally occur during vagus nerve stimulation (VNS) used in epileptic patients. As they can be potentially life-threatening, it is important to detect them, and this is why an intraoperative test is performed during the implantation. Few cases of asystole during this test have been described. Only one patient with late-onset bradyarrythmia caused by VNS has been reported. This patient had been implanted 2 years and 4 months before the episode. We present another case of late asystole in a patient whose VNS had been implanted 9 years before the arrhythmia onset. In our patient, each run of stimulation produced bradyarrhythmias and very often severe asystolia due to atrium-ventricular block.     

Cortical tonotopic map plasticity and behavior

Central topographic representations of sensory epithelia have a genetic basis, but are refined by patterns of afferent input and by behavioral demands. Here we review such experience-driven map development and plasticity, focusing on the auditory system, and giving particular consideration to its adaptive value and to the putative mechanisms involved. Recent data have challenged the widely held notion that only the developing auditory brain can be influenced by changes to the prevailing acoustic environment, unless those changes convey information of behavioral relevance. Specifically, it has been shown that persistent exposure of adult animals to random, bandlimited, moderately loud sounds can lead to a reorganization of auditory cortex not unlike that following restricted hearing loss. The mature auditory brain is thus more plastic than previously supposed, with potentially troubling consequences for those working or living in noisy environments, even at exposure levels considerably below those presently considered just-acceptable.     

Outcome measurement after vagal nerve stimulation therapy: proposal of a new classification

PURPOSE: Vagal nerve stimulation (VNS) is an adjunctive palliative therapy for refractory epilepsy. Effects of treatment are varied and some, such as the use of an external magnet for seizure termination, are unique to VNS. No accepted standard exists for outcome measurement after VNS treatment. We present a novel classification for outcome, which includes assessment of both seizure frequency and severity in VNS-treated patients. METHODS: We devised a classification system modeled on the Engel classification for surgically treated patients, but tailored for use in VNS therapy, which incorporates five classes of outcome. We retrospectively reviewed VNS-treated patients in our centre, and used the data to illustrate our system and compare it with the Engel model. RESULTS: With this system, 48 patients (mean age, 30 years) were followed up over a median of 18 months. Seventy-eight percent had partial epilepsy. Sixteen and a half percent experienced class I outcome (>80% seizure-frequency reduction). Twenty percent had class II improvement (50-79% seizure-frequency reduction). One-third had no improvement (class V). The remaining patients comprised class III (seizure-frequency reduction <50%) or class IV (magnet benefit alone) outcomes. Class I-III outcomes were further subdivided according to effects on ictal or postictal severity. CONCLUSIONS: We propose a new classification, which can be used for all epilepsies and which reflects outcome measures beyond seizure-frequency reduction alone. Use of this system would allow greater comparison between future studies of VNS therapy.     

Vagal nerve stimulation induces intermittent hypocapnia

PURPOSE: To study whether respiratory alteration caused by vagal nerve stimulation (VNS) can change end-tidal carbon dioxide (EtCO2) levels. METHODS: We performed polygraphic recordings including capnographic monitoring during daytime sleep on adults with VNS therapy. RESULTS: Ten of 13 patients showed VNS-induced alterations in the frequency or amplitude of respiration. Five patients had a consistent increase in respiratory rate with a simultaneous, consistent and significant decrease (p < 0.01; 5-22%) in EtCO2 during VNS. Three subjects showed occasional decreases in EtCO2 during VNS, and two showed no clearly detectable VNS-related EtCO2 changes. CONCLUSIONS: Our findings suggest that VNS may alter brain CO2 levels through changes in respiration. Because carbon dioxide (CO2) has potent effects on various brain functions, it is possible that these transient CO2 changes may have an effect on the state transitions between interictal and preictal states.     

The effects of vagus nerve stimulation on decision-making

Subcortical and brainstem structures are increasingly becoming recognized as important contributors to higher cognitive functioning. Decision-making is one such function, particularly as viewed within the framework of the somatic marker hypothesis (SMH). The SMH views the participation in decision-making by the body proper as integral to emotional biasing and hence key to choosing in an advantageous manner. This study focuses on the vagus nerves as a possible conduit for somatic afferent signals pertinent to decision-making. We tested eight epileptic patients with implanted left vagus nerve stimulators. To assess decision-making we used the gambling task, which is sensitive to real-life decision-making deficits. Using a counterbalanced design, each participant performed the gambling task under a condition in which low-level vagus nerve stimulation (VNS) was covertly delivered, and another condition in which no VNS was delivered. Participants showed improved performance, that is, made more advantageous choices, in the stimulated relative to the un-stimulated condition. Although these results should be viewed as preliminary, they suggest that the vagus nerve is a conduit for afferent somatic signals that can influence decision-making.     

Short trains of transcutaneous auricular vagus nerve stimulation (taVNS) have parameter-specific effects on heart rate

Background

Optimal parameters of transcutaneous auricular vagus nerve stimulation (taVNS) are still undetermined. Given the vagus nerve's role in regulating heart rate (HR), it is important to determine safety and HR effects of various taVNS parameters.

Mismatch negativity analysis in drug-resistant epileptic patients implanted with vagus nerve stimulator

It is well known that some epileptic patients does not respond to conventional treatments, despite multiple combination of antiepileptic drugs, and they are therefore considered drug-resistant. For these patients, vagal nerve stimulation (VNS) represents a successful alternative to traditional therapy, and it is generally well tolerated; beside benefits on seizure frequency, VNS showed positive effects on cognition and mood. Aim of this study was to investigate short-term memory changes in a group of 12 patients implanted with VNS, through Mismatch Negativity wave (MMN). After 1 year of follow-up, MMN latencies and amplitudes did not show significant changes following VNS implantation, independently on current intensity, as compared with pre-implantation values. In two patients, MMN values, which were abnormal before VNS implantation, showed a major reduction in latency and an increase in amplitude after implantation, suggesting a likely positive effect of VNS on pre-attentive processes investigated by MMN.     

Right-sided vagus nerve stimulation as a treatment for refractory epilepsy in humans

PURPOSE: We present three children who underwent right-sided vagus nerve stimulation (R-VNS). This treatment option for people with refractory epilepsy has not been described in children. METHODS: We reviewed our database of >350 patients implanted with vagus nerve stimulators and now describe our experience in three patients with R-VNS for the treatment of intractable seizures. All three patients improved dramatically with left-sided vagus nerve stimulation (L-VNS), but the devices had to be removed because of infection. The patients were thought to be at high risk for nerve injury if they were reapproached for L-VNSs; therefore R-VNSs were implanted. RESULTS: All three patients with an R-VNS had a reduction in seizures. Our first patient has had an R-VNS for 5 years; he has been seizure free for >2 years on R-VNS monotherapy. The second patient had an R-VNS for 8 months. His seizure control improved slightly, but not as dramatically as with L-VNS. The third child has had an R-VNS for >7 months and has cessation of his most disabling seizure type (generalized tonic-clonic seizures). None of the patients had cardiac side effects from therapeutic R-VNS. However, two of the three patients had respiratory events with R-VNS. CONCLUSIONS: VNS is known to be an effective treatment in pharmacoresistant epilepsy. R-VNS should be considered if a patient has significant benefit from L-VNS but is unable to continue with L-VNS. R-VNS appears also to have antiepilepsy effects. Additionally, our case report suggests that in some patients, a differential response is found regarding seizure control with R-VNS or L-VNS, raising the question whether L-VNS failures should pursue a trial of R-VNS. Patients should be cautioned and monitored for reactive airway disease if they undergo R-VNS. More research is needed to compare the effects of right- and left-sided VNS on cardiac and pulmonary function in humans and to determine which has the best antiseizure effect.     

迷走神经刺激术在难治性癫痫领域的临床进展

迷走神经刺激术(vagus nerve stimulation,VNS)是通过躯体性刺激治疗神经-精神疾病的一种方法.自1883年以来,许多学者对VNS的抗癫痫作用进行了研究,最终认为VNS是治疗难治性癫痫的新途径[1-3].1997年7月VNS首次通过美国食品药物管理局(FDA)认证,用于成人和年龄大于12岁青少年癫痫的辅助治疗.目前为止全球已经有超过100 000的患者接受了VNS治疗[4].     

Effect of vagal nerve stimulation on interictal epileptiform discharges: a scalp EEG study

PURPOSE: To investigate the effects of acute vagal nerve stimulation (VNS) on interictal epileptiform discharges (IEDs). METHODS: Fifteen epilepsy patients, all of whom had been treated with VNS for > or =6 months, entered the study. In each subject, the absolute number of IEDs was counted at the baseline period (BP), the stimulation period (SP), six interstimulation periods (IPs), and the prestimulation period (PP), by using an original paradigm. The number of IEDs at the BP and the PP was compared with the number of IEDs at the SP and IPs. The results were correlated with other variables (the duration of VNS, the value of the output current, the duration of epilepsy, the type of epilepsy, the effect of VNS, and the effect of extrastimulation). RESULTS: We observed a significantly higher reduction in the number of IEDs in the SP and all the IPs as compared with the BP. We noticed a significantly higher reduction in the number of IEDs in the SP and in the first IP as compared with the PP. The reduction of IEDs was greater in patients who responded to VNS (>50% reduction of all seizures) and in patients who responded positively to magnetic extrastimulation. There were no other significant results in the reduction of IEDs when comparing other variables. CONCLUSIONS: Short-term VNS reduces IEDs significantly. The reduction is most prominent during the SP (i.e., when the pulse generator is active). The value of reduction of IEDs is higher in patients who respond to VNS and in patients with positive experiences with magnetic extrastimulation. These results can be useful in predicting the effect of VNS.     

迷走神经刺激术治疗顽固性癫痫初步探讨

目的 探讨迷走神经刺激术治疗顽固性癫痫的治疗效果.方法 对21例顽固性癫痫患者进行迷走神经刺激手术治疗,术后2周开机,分次调试参数,脉冲发生器输出电流从0.25 mA逐渐增加,但不超过3.0 mA,刺激时间为30 s,间歇5 min,信号频率为20～30 Hz,脉宽为250～1000μs.对治疗效果进行随访,分析治疗效果.结果 经4-16个月刺激,McHugh Ⅰ级3例,Ⅱ级7例,Ⅲ级9例,Ⅴ级2例.其中10例患者癫痫发作减少50%以上.结论 迷走神经刺激术治疗顽固性癫痫是一种相对安全、有效的治疗方法 .     

Cerebral activation during vagus nerve stimulation: a functional MR study

PURPOSE: To study the short-term effects of vagus nerve stimulation (VNS) on brain activation and cerebral blood flow by using functional magnetic resonance imaging (fMRI). METHODS: Five patients (three women, two men; mean age, 35.4 years) who were treated for medically refractory epilepsy with VNS, underwent fMRI. All patients had a nonfocal brain MRI. The VNS was set at 30 Hz, 0.5-2.0 mA for intervals of activation of 30 s on and 30 s off, during which the fMRI was performed. Statistical parametric mapping (SPM) was used to determine significant areas of activation or inhibition during vagal nerve stimulation (p < 0.05). RESULTS: VNS-induced activation was detected in the thalami bilaterally (left more than right), insular cortices bilaterally, ipsilateral basal ganglia and postcentral gyri, right posterior superior temporal gyrus, and inferomedial occipital gyri (left more than right). The most robust activation was seen in the thalami (left more than right) and insular cortices. Conclusions: VNS-induced thalamic and insular cortical activation during fMRI suggests that these areas may play a role in modulating cerebral cortical activity, and the observed decrease in seizure frequency in patients who are given VNS may be a consequence of this increased activation.     

Late onset bradyarrhythmia during vagus nerve stimulation

Vagus nerve stimulation (VNS) is widely used to treat refractory epilepsy. It is usually safe and has few side effects. Cardiac arrhythmia has been reported during lead tests performed during implantation of the device, but never during regular treatment. We report here a case where vagally induced bradyarrhythmia, perfectly correlated with the stimulation periods, suddenly occurred two years and four months after the VNS implantation. The diagnosis was based on the appearance of syncope-like episodes. No specific cause could be found to explain the appearance of the episodes. To our knowledge, this is the first report on this severe and life-threatening side effect of VNS and should alert clinicians to its possibility. However, considering the large number of VNS implantations performed worldwide, it must be regarded as an extremely rare complication.     

Brain-clinical signatures for vagus nerve stimulation response

Aim

Vagus nerve stimulation (VNS) is a valuable treatment for drug-resistant epilepsy (DRE) without the indication of surgical resection. The clinical heterogeneity of DRE has limited the optimal indication of choice and diagnosis prediction. The study aimed to explore the correlations of brain-clinical signatures with the clinical phenotype and VNS responsiveness.

Methods

A total of 89 DRE patients, including VNS- (n = 44) and drug-treated (n = 45) patients, were retrospectively recruited. The brain-clinical signature consisted of demographic information and brain structural deformations, which were measured using deformation-based morphometry and presented as Jacobian determinant maps. The efficacy and presurgical differences between these two cohorts were compared. Then, the potential of predicting VNS response using brain-clinical signature was investigated according to the different prognosis evaluation approaches.

Results

The seizure reduction was higher in the VNS-treated group (42.50%) as compared to the drug-treated group (12.09%) (p = 0.11). Abnormal imaging representation, showing encephalomalacia (p_corrected = 0.03), was commonly observed in the VNS-treated group (p = 0.04). In the patients treated with VNS, the mild/subtle brain abnormalities indicated higher seizure frequency (p = 0.03) and worse VNS response (p = 0.04). The partial least square regression analysis showed a moderate prediction potential of brain-clinical signature for VNS response (p < 0.01). The increase in the pre-VNS seizure frequency and structural etiology could indicate a worse prognosis (higher McHugh classification).

Conclusion

The brain-clinical signature illustrated its clinical potential in predicting the VNS response, which might allow clinicians to personalize treatment decisions for DRE patients.     

Complications of vagal nerve stimulation for drug-resistant epilepsy: A single center longitudinal study of 143 patients

PurposeTo longitudinally study surgical and hardware complications to vagal nerve stimulation (VNS) treatment in patients with drug-resistant epilepsy.MethodsIn a longitudinal retrospective study, we analyzed surgical and hardware complications in 143 patients (81 men and 62 women) who between 1994 and 2010 underwent implantation of a VNS-device for drug-resistant epilepsy. The mean follow-up time was 62 ± 46 months and the total number of patient years 738.Results251 procedures were performed on 143 patients. 16.8% of the patients were afflicted by complications related to surgery and 16.8% suffered from hardware malfunctions. Surgical complications were: superficial infection in 3.5%, deep infection needing explantation in 3.5%, vocal cord palsy in 5.6%, which persisted in at least 0.7% for over one year, and other complications in 5.6%. Hardware-related complications were: lead fracture in 11.9% of patients, disconnection in 2.8%, spontaneous turn-off in 1.4% and stimulator malfunction in 1.4%. We noted a tendency to different survival times between the two most commonly used lead models as well as a tendency to increased infection rate with increasing number of stimulator replacements.ConclusionIn this series we report on surgical and hardware complications from our 16 years of experience with VNS treatment. Infection following insertion of the VNS device and vocal cord palsy due to damage to the vagus nerve are the most serious complications related to the surgery. Avoiding unnecessary reoperations in order to reduce the appearances of these complications are of great importance. It is therefore essential to minimize technical malfunctions that will lead to additional surgery. Further studies are needed to evaluate the possible superiority of the modified leads.