A resting-state functional MRI study on the effect of vagal nerve stimulation on spontaneous regional brain activity in drug-resistant epilepsy patients.

PURPOSE: To explore the effect of vagal nerve stimulation (VNS) on spontaneous brain activity in patients with drug-resistant epilepsy (DRE). METHODS: 15 patients and eight healthy controls (HC) were enrolled and scanned by resting-state functional MRI to investigate changes in the fractional amplitude of low-frequency fluctuation (fALFF) and regional homogeneity (ReHo). A two-sample t-test or paired sample t-test was used to compare activity between the HCs, preoperative patients (EP-pre), and postoperative patients (EP-post). We also performed correlation analyses to examine the seizure improvement ratio. RESULTS: The voxel-level analyses indicated that, compared with the HC, the EP-pre group exhibited decreased or increased fALFF and ReHo in the frontal cortex, temporal cortex, precentral/postcentral gyrus, amygdala, insula, cerebellum, and lingual gyrus. Furthermore, compared with the EP-pre group, the EP-post group exhibited decreased or increased fALFF and ReHo in the frontal cortex, temporal cortex, precentral gyrus, insula, anterior/median cingulate gyri, and cerebellum. The regions of interest-level analyses indicated that, compared with HC, the EP-pre group exhibited decreased fALFF or ReHo in the caudate nucleus, supramarginal gyrus, precuneus and middle temporal gyrus. Furthermore, compared with the EP-pre group, the EP-post group exhibited increased fALFF or ReHo in the olfactory cortex, gyrus rectus, and superior temporal gyrus. Increased ReHo in the right superior or middle temporal gyrus was positively correlated with the improvement ratio. CONCLUSIONS: Altered regional activity in DRE patients was reorganized after 3 months of stimulation. Increased ReHo in the right superior or middle temporal gyrus was implicated in VNS-induced improvement in seizure frequency.

Vagus nerve stimulation for patients with refractory epilepsy: Demographic features and neuropsychological outcomes of the VNS Taiwan child neurology society database.

OBJECTIVES: Vagus nerve stimulation (VNS) is an established adjunctive therapy for medically refractory epilepsy, which is commonly associated with cognitive impairment, especially in children in whom seizures may disrupt development that is essential to their intellectual and social maturation. The Taiwan Child Neurology Society intends to expand the use of VNS by reporting the experience in a nationwide population, displaying the demographic features and neuropsychological outcomes of VNS. METHODS: The enrollment included 105 patients of all ages and seizure types who underwent VNS implantation for refractory epilepsy. Basic data included etiology, past history, seizure phenotypes, and epileptiform syndromes. For efficacy analysis, seizure frequencies were recorded at the baseline and at 3, 12, 24, and 36 months after VNS implantation. For psychological assessment, intelligence quotients (IQ) and Parental Stress Index (PSI) scores were evaluated before and after the VNS. RESULTS: During the study period, 95 patients with VNS had followed seizure frequency, IQ and PSI recording. After implantation, there was a decreased frequency at 3 (P < .001), 12 (P < .001), 24 (P = .010), and 36 (P < .01) months. After implantation, the reduction rate (0-50%) of seizure frequency ranged around 26.1-36.1% from 3 to 36 months. For PSI scores, the VNS significantly improved the PSI- total score (P = .001) and PSI-parent domain (P = .001) but not the PSI-children domain (P = .052). No significant improvement in the IQ test performance was observed. CONCLUSIONS: This prospective nationwide database of VNS in Taiwan indicates long-term efficacy of VNS therapy, which has achieved a trend of seizure frequency reduction over a period of up to 36 months. It also shows the trend of decreased parental stress after VNS implantation.

Vagus nerve stimulation for drug-resistant epilepsy.

Vagus nerve stimulation (VNS) is a neuromodulatory therapeutic option for drug-resistant epilepsy. In randomised controlled trials, VNS implantation has resulted in over 50% reduction in seizure frequency in 26%-40% of patients within 1 year. Long-term uncontrolled studies suggest better responses to VNS over time; however, the assessment of other potential predictive factors has led to contradictory results. Although initially designed for managing focal seizures, its use has been extended to other forms of drug-resistant epilepsy. In this review, we discuss the evidence supporting the use of VNS, its impact on seizure frequency and quality of life, and common adverse effects of this therapy. We also include practical guidance for the approach to and the management of patients with VNS in situ.

Vagus nerve stimulation reverses the extinction impairments in a model of PTSD with prolonged and repeated trauma.

We have shown that vagus nerve stimulation (VNS) enhances extinction of conditioned fear and reduces anxiety in rat models of PTSD using moderate stress. However, it is still unclear if VNS can be effective in enhancing extinction of severe fear after prolonged and repeated trauma. Severe fear was induced in adult male rats by combining single prolonged stress (SPS) and protracted aversive conditioning (PAC). After SPS and PAC procedures, rats were implanted with stimulating cuff electrodes, exposed to five days of extinction training with or without VNS, and then tested for extinction retention, return of fear in a new context and reinstatement. The elevated plus maze, open field and startle were used to test anxiety. Sham rats showed no reduction of fear during extensive extinction training. VNS-paired with extinction training reduced freezing at the last extinction session by 70% compared to sham rats. VNS rats exhibited half as much fear as shams, as well as less fear renewal. Sham rats exhibited significantly more anxiety than naive controls, whereas VNS rats did not. These results demonstrate that VNS enhances extinction and reduces anxiety in a severe model of PTSD that combined SPS and a conditioning procedure that is 30 times more intense than the conditioning procedures in previous VNS studies. The broad utility of VNS in enhancing extinction learning in rats and the strong clinical safety record of VNS suggest that VNS holds promise as an adjuvant to exposure-based therapy in people with PTSD and other complex forms of this condition.

Vagus nerve stimulation for 6- to 12-year-old children with refractory epilepsy: Impact on seizure frequency and parenting stress index.

OBJECTIVES: Refractory epilepsy (RE) is frequently associated with neuropsychological impairment in children and may disrupt their social development. Vagus nerve stimulation (VNS) had been reported to have beneficial effects on behavioral outcomes. The aim of this study was to compare Parenting Stress Index (PSI) scores before and after VNS device implantation in children with RE, especially those who experienced seizure frequency reduction. METHODS: We conducted a one-group pretest-posttest study in school age children with RE. Seizure frequency and PSI were recorded at 12months after VNS device implantation. RESULTS: Treatment with VNS was significantly associated with reduced seizure frequency and parental stress as measured by PSI. Factors contributing to seizure frequency included idiopathic/cryptogenic etiology and neurobehavioral comorbidities. In children with reduced seizure frequency, statistically significant improvements in the child domain of the PSI on the subscales of mood and reinforces parent were found. In the parent domain, the scores for social isolation were reduced. CONCLUSIONS: Treatment with VNS was significantly associated with reduced seizure frequency and improved PSI scores, especially within the child domain on the mood and reinforces parent subscales. These findings suggest that VNS reduced not only seizure frequency but also the psychological burden on children with RE.

A 6-Year Follow-up Study of Vagus Nerve Stimulation Effect on Quality of Life in Treatment-Resistant Depression: A Pilot Study.

OBJECTIVES: Treatment-resistant depression (TRD) carries a major burden on those affected by this disease and significantly impacts their quality of life (QOL). Vagus nerve stimulation (VNS) has showed promising results on symptoms, but its impact on QOL remains underresearched. This study aims to evaluate the long-term effects of VNS on both QOL and clinical symptoms for TRD patients, through a naturalistic 6-year follow-up. METHOD: Outpatients with confirmed TRD were enrolled to receive VNS. None of the patients enrolled left the study or was lost at follow-up. Patients were evaluated at 1, 3, 6, 12, 24, 36, 48, 60, and 72 months for a total of 10 assessments using the 36 item Short Form questionnaire, Hamilton Rating Scale for Depression and Hamilton Anxiety Rating Scale. RESULTS: Ten patients were enrolled with a mean age of 50 years. This study shows a clinically and statistically significant improvement of the mental QOL (P = 0.012), physical QOL (P < 0.002), depressive symptoms (P < 0.001), and anxiety symptoms (P < 0.001). CONCLUSIONS: This long-term naturalistic study is the first to demonstrate that the therapeutic effect of VNS on TRD goes beyond clinical symptoms to improve the daily QOL of those affected.

Effects of vagus nerve stimulation on extinction of conditioned fear and post-traumatic stress disorder symptoms in rats.

Exposure-based therapies help patients with post-traumatic stress disorder (PTSD) to extinguish conditioned fear of trauma reminders. However, controlled laboratory studies indicate that PTSD patients do not extinguish conditioned fear as well as healthy controls, and exposure therapy has high failure and dropout rates. The present study examined whether vagus nerve stimulation (VNS) augments extinction of conditioned fear and attenuates PTSD-like symptoms in an animal model of PTSD. To model PTSD, rats were subjected to a single prolonged stress (SPS) protocol, which consisted of restraint, forced swim, loss of consciousness, and 1 week of social isolation. Like PTSD patients, rats subjected to SPS show impaired extinction of conditioned fear. The SPS procedure was followed, 1 week later, by auditory fear conditioning (AFC) and extinction. VNS or sham stimulation was administered during half of the extinction days, and was paired with presentations of the conditioned stimulus. One week after completion of extinction training, rats were given a battery of behavioral tests to assess anxiety, arousal and avoidance. Results indicated that rats given SPS 1 week prior to AFC (PTSD model) failed to extinguish the freezing response after eleven consecutive days of extinction. Administration of VNS reversed the extinction impairment and attenuated reinstatement of the conditioned fear response. Delivery of VNS during extinction also eliminated the PTSD-like symptoms, such as anxiety, hyperarousal and social avoidance for more than 1 week after VNS treatment. These results provide evidence that extinction paired with VNS treatment can lead to remission of fear and improvements in PTSD-like symptoms. Taken together, these findings suggest that VNS may be an effective adjunct to exposure therapy for the treatment of PTSD.

Vagus Nerve Stimulation Enhances Extinction of Conditioned Fear in Rats and Modulates Arc Protein, CaMKII, and GluN2B-Containing NMDA Receptors in the Basolateral Amygdala.

Vagus nerve stimulation (VNS) enhances the consolidation of extinction of conditioned fear. High frequency stimulation of the infralimbic cortex (IL) produces long-term potentiation in the basolateral amygdala (BLA) in rats given VNS-paired extinction training, whereas the same stimulation produces long-term depression in sham-treated rats. The present study investigated the state of synaptic plasticity-associated proteins in the BLA that could be responsible for this shift. Male Sprague-Dawley rats were separated into 4 groups: auditory fear conditioning only (fear-conditioned); fear conditioning + 20 extinction trials (extended-extinction); fear conditioning + 4 extinction trials paired with sham stimulation (sham-extinction); fear conditioning + 4 extinction trials paired with VNS (VNS-extinction). Freezing was significantly reduced in extended-extinction and VNS-extinction rats. Western blots were used to quantify expression and phosphorylation state of synaptic plasticity-associated proteins such as Arc, CaMKII, ERK, PKA, and AMPA and NMDA receptors. Results show significant increases in GluN2B expression and phosphorylated CaMKII in BLA samples from VNS- and extended-extinction rats. Arc expression was significantly reduced in VNS-extinction rats compared to all groups. Administration of the GluN2B antagonist ifenprodil immediately after fear extinction training blocked consolidation of extinction learning. Results indicate a role for BLA CaMKII-induced GluN2B expression and reduced Arc protein in VNS-enhanced extinction.

Vagus nerve stimulation modulates visceral pain-related affective memory.

Within a biopsychosocial model of pain, pain is seen as a conscious experience modulated by mental, emotional and sensory mechanisms. Recently, using a rodent visceral pain assay that combines the colorectal distension (CRD) model with the conditioned place avoidance (CPA) paradigms, we measured a learned behavior that directly reflects the affective component of visceral pain, and showed that perigenual anterior cingulate cortex (pACC) activation is critical for memory processing involved in long-term visceral affective state and prediction of aversive stimuli by contextual cue. Electrical vagus nerve stimulation (VNS) has become an established therapy for treatment-resistant epilepsy. VNS has also been shown to enhance memory performance in rats and humans. High-intensity VNS (400 µA) immediately following conditional training significantly increases the CRD-induced CPA scores, and enhanced the pain affective memory retention. In contrast, VNS (400 µA) had no effect on CPA induced by non-nociceptive aversive stimulus (U69,593). Low-intensity VNS (40 µA) had no effect on CRD-induced CPA. Electrophysiological recording showed that VNS (400 µA) had no effect on basal and CRD-induced ACC neuronal firing. Further, VNS did not alter CRD-induced visceral pain responses suggesting high intensity VNS facilitates visceral pain aversive memory independent of sensory discriminative aspects of visceral pain processing. The findings that vagus nerve stimulation facilities visceral pain-related affective memory underscore the importance of memory in visceral pain perception, and support the theory that postprandial factors may act on vagal afferents to modulate ongoing nature of visceral pain-induced affective disorder observed in the clinic, such as irritable bowel syndrome.

Willingness to accept and pay for implantable tinnitus treatments: a survey.

OBJECTIVES: At present, there is no cure for tinnitus. Neurostimulation techniques have shown great promise, but it is uncertain whether they will gain acceptance because of their invasive nature. We have previously demonstrated that pairing acoustic stimuli with vagus nerve stimulation (VNS) also has potential as a viable tinnitus treatment approach. METHODS: We conducted a survey on tinnitus sufferers that emphasized questions related to a willingness to pay for the treatment of tinnitus, including VNS. Four hundred thirty-nine individuals responded to an Internet survey modeled after a recent study by Tyler. RESULTS: The average age was about 47 years. Ninety-four percent reported that they had health insurance. Almost 40% had spent between $500 and $10,000 on tinnitus therapies. Almost three-fourths said that they would be willing to have a device implanted if it reduced tinnitus annoyance by half. About 70% of those with very loud tinnitus would be willing to have a temporary implant, and about 60% would be willing to have a permanent implant even if the device suppressed their tinnitus by only half of its annoyance. Only 10% of patients with SOFT tinnitus would be willing to have a permanent implant if the therapy suppressed their tinnitus by only half of its annoyance. CONCLUSIONS: We conclude that implanted devices, such as a VNS, will be an acceptable form of tinnitus treatment for many who suffer from tinnitus. The results of this survey indicate that VNS tone pairing would be an acceptable therapeutic solution for individuals with moderate to severe tinnitus and should be developed for the market.

Clinical outcomes, quality of life, and costs associated with implantation of vagus nerve stimulation therapy in pediatric patients with drug-resistant epilepsy.

BACKGROUND: VNS (Vagus Nerve Stimulation Therapy) is approved in the USA to treat refractory epilepsy as adjunctive to antiepileptic drugs (AEDs) in patients ≥12 years with complex partial seizures. AIMS: To evaluate clinical outcomes, quality-adjusted life years (QALY), and costs associated with VNS in pediatric patients with drug-resistant epilepsy in a real-world setting. METHODS: A retrospective analysis was conducted using Medicaid data (USA). Patients had ≥1 neurologist visits with epilepsy diagnosis (ICD-9 345.xx, 780.3x), ≥1 procedure claims for VNS implantation, ≥1 AEDs, ≥6-months of Pre- and Post-VNS continuous enrollment. Pre-VNS period was 6-months and Post-VNS period extended from implantation until device removal, death, Medicaid disenrollment, or study end (up to 3 years). Incidence rate ratios (IRR) and costs ($2010) were estimated. QALYs were estimated using number of seizure-related events. RESULTS: For patients 1-11 years old (N = 238), hospitalizations and emergency room visits were reduced Post-VNS vs. Pre-VNS (adjusted IRR = 0.73 [95% CI: 0.61-0.88] and 0.74 [95% CI: 0.65-0.83], respectively). Average total healthcare costs were lower Post-VNS vs. Pre-VNS ($18,437 vs. $18,839 quarterly [adjusted p = 0.052]). For patients 12-17 years old (N = 207), hospitalizations and status epilepticus events were reduced Post-VNS vs. Pre-VNS (adjusted IRR = 0.43 [95% CI: 0.34-0.54] and 0.25 [95% CI: 0.16-0.39], respectively). Average total healthcare costs were lower Post-VNS vs. Pre-VNS period ($14,546 vs. $19,695 quarterly [adjusted p = 0.002]). Lifetime QALY gain after VNS was 5.96 (patients 1-11 years) and 4.82 years (patients 12-17 years). CONCLUSIONS: VNS in pediatric patients is associated with decreased resource use and epilepsy-related events, cost savings, and QALY gain.

The emerging use of brain stimulation treatments for psychiatric disorders.

OBJECTIVE: The aim of this study was to review the current state of development and application of a wide range of brain stimulation approaches in the treatment of psychiatric disorders. METHOD: The approaches reviewed include forms of minimally invasive magnetic and electrical stimulation, seizure induction, implanted devices and several highly novel approaches in early development. RESULTS: An extensive range of brain stimulation approaches are now being widely used in the treatment of patients with psychiatric disorders, or actively investigated for this use. Both vagal nerve stimulation (VNS) and repetitive transcranial magnetic stimulation (rTMS) have been introduced into clinical practice in some countries. A small body of research suggests that VNS has some potentially long-lasting antidepressant effects in a minority of patients treated. rTMS has now been extensively investigated for over 15 years, with a large body of research now supporting its antidepressant effects. Further rTMS research needs to focus on defining the most appropriate stimulation methods and exploring its longer term use in maintenance protocols. Very early data suggest that magnetic seizure therapy (MST) has promise in the treatment of patients referred for electroconvulsive therapy: MST appears to have fewer side effects and may have similar efficacy. A number of other approaches including surgical and alternative forms of electrical stimulation appear to alter brain activity in a promising manner, but are in need of evaluation in more substantive patient samples. CONCLUSIONS: It appears likely that the range of psychiatric treatments available for patients will grow over the coming years to progressively include a number of novel brain stimulation techniques.

The application of vagus nerve stimulation and deep brain stimulation in depression.

Despite the progress in the pharmacotherapy of depression, there is a substantial proportion of treatment-resistant patients. Recently, reversible invasive stimulation methods, i.e. vagus nerve stimulation (VNS) and deep brain stimulation (DBS), have been introduced into the management of treatment-resistant depression (TRD). VNS has already received regulatory approval for TRD. This paper reviews the available clinical evidence and neurobiology of VNS and DBS in TRD. The principle of VNS is a stimulation of the left cervical vagus nerve with a programmable neurostimulator. VNS was examined in 4 clinical trials with 355 patients. VNS demonstrated steadily increasing improvement with full benefit after 6-12 months, sustained up to 2 years. Patients who responded best had a low-to-moderate antidepressant resistance. However, the primary results of the only controlled trial were negative. DBS involves stereotactical implantation of electrodes powered by a pulse generator into the specific brain regions. For depression, the targeted areas are the subthalamic nucleus, internal globus pallidus, ventral internal capsule/ventral striatum, the subgenual cingulated region, and the nucleus accumbens. Antidepressant effects of DBS were examined in case series with a total number of 50 TRD patients. Stimulation of different brain regions resulted in a reduction of depressive symptoms. The clinical data on the use of VNS and DBS in TRD are encouraging. The major contribution of the methods is a novel approach that allows for precise targeting of the specific brain areas, nuclei and circuits implicated in the etiopathogenesis of neuropsychiatric disorders. For clinical practice, it is necessary to identify patients who may best benefit from VNS or DBS.

Time perception in patients with major depressive disorder during vagus nerve stimulation.

BACKGROUND: Affective disorders may affect patients' time perception. Several studies have described time as a function of the frontal lobe. The activating eff ects of vagus nerve stimulation on the frontal lobe might also modulate time perception in patients with major depressive disorder (MDD). METHODS: Time perception was investigated in 30 patients with MDD and in 7 patients with therapy-resistant MDD. In these 7 patients, a VNS system was implanted and time perception was assessed before and during stimulation. A time estimation task in which patients were asked "How many seconds have passed?" tested time perception at 4 defined time points (34 s, 77 s, 192 s and 230 s). The differences between the estimated and actual durations were calculated and used for subsequent analysis. RESULTS: Patients with MDD and healthy controls estimated the set time points relatively accurately. A general linear model revealed a significant main eff ect of group but not of age or sex. The passing of time was perceived as significantly slower in patients undergoing VNS compared to patients with MDD at all time points (T34: t = − 4.2; df = 35; p < 0.001; T77: t = − 4.8; df = 35; p < 0.001; T192: t = − 2.0; df = 35; p = 0.059; T230 t = −2.2; df = 35; p = 0.039) as well as compared to healthy controls (at only T77: t = 4.1; df = 35; p < 0.001). There were no differences in time perception with regard to age, sex or polarity of depression (uni- or bipolar). CONCLUSIONS: VNS is capable of changing the perception of time. This discovery furthers the basic research on circadian rhythms in patients with psychiatric disorders.

Neuropsychologic effects of neuromodulation techniques for treatment-resistant depression: a review.

Electroconvulsive therapy (ECT) and ablative neurosurgical procedures are established interventions for treatment-resistant depression (TRD), but their use may be limited in part by neuropsychological adverse effects. Additional neuromodulation strategies are being developed that aim to match or exceed the efficacy of ECT/ablative surgery with a better neurocognitive side effect profile. In this review, we briefly discuss the neurocognitive effects of ECT and ablative neurosurgical procedures, then synthesize the available neurocognitive information for emerging neuromodulation therapies, including repetitive transcranial magnetic stimulation, magnetic seizure therapy, transcranial direct current stimulation, vagus nerve stimulation, and deep brain stimulation. The available evidence suggests these procedures may be more cognitively benign relative to ECT or ablative neurosurgical procedures, though further research is clearly needed to fully evaluate the neurocognitive effects, both positive and negative, of these novel neuromodulation interventions.

Longer-term effects of implanted vagal nerve stimulation.

Vagal nerve stimulation (VNS) is a non-pharmacologic therapeutic intervention approved in adults and children with neuropsychiatric disorders. Studies conducted over the past 20 years have demonstrated that VNS results in immediate and longer-term changes in brain regions implicated in neuropsychiatric disorders, such as the thalamus, cerebellum, orbitofrontal cortex, limbic system, hypothalamus, and medulla with vagus innervations. This review summarizes the effects of longer-term implanted VNS and how the incorporation of this non-pharmacologic therapeutic management in the treatment regime can be beneficial to address the needs of patients who are unable to tolerate medications and/or undergo surgery and do not respond to pharmacologic therapies. We also highlight the therapeutic efficacy of longer-term implanted VNS, safety, tolerability, patient acceptance, adherence, and adverse events, if any, in adults and children in this modality of treatment.