Vagus nerve stimulation (VNS)
Summary about the safety and efficacy of VNS and transcutaneous VNS (tVNS)
Safety of VNS and tVNS
The best indication of the safety of implanted VNS are the approvals of this treatment method by FDA (1997) and EU (1994), first for epilepsy and then for depression (2005). Also the over two decades long follow-up time of the usage of implanted VNS has not showed any significant adverse effects. In addition, the evidence of the long-time clinical use of VNS supported to claim VNS as a safe and effective therapy for epilepsy and classiﬁed it as Level I in 1999 by the American Academy of Neurology.
Similarly, the firstly developed transcutaneous vagal nerve stimulation (tVNS) device, ”Nemos” (of Cerbomed GMBH), received CE approval in 2010 (CE1275). ”NEMOS” is using an ear electrode. The same is true with our first generation ”SaluStim” device: this transcutaneous electrical stimulation device received CE approcal (EC Certificate ) in Sept 2013 (Certificate registration No.: SX 600848100001).
CE marking is an indication that a medical device complies with essential health and safety. As tVNS shares the modes of actions of implanted VNS it seems justified to state that stimulation with a tVNS device is at least as safe as stimulation with implanted VNS. This statement can be further stressed after the studies of Kreuzer et al (2012) and Lehtimäki et al (2013), Ylikoski et al (2017), which demonstrate that tVNS device is safe to use in patients.
Efficacy of tVNS
The efficacy of tVNS is mainly based on earlier studies of implanted VNS (randomized placebo controlled trials) indicating that 30% of epilepsy patients would have a greater than 50% reduction of seizures and about 50% of patients experience a 40% or greater reduction in seizure frequency and severity (Beekwilder and Beems 2010). In the only published study of the use of tVNS in epilepsy (Stefan et al 2012), the authors state that the tVNS stimulation is a safe and well-tolerated method for relatively long periods, and might be an alternative treatment option for patients with epilepsy. In addition, our recent pilot study shows that tVNS, if combined with sound therapy, significantly reduces the severity of tinnitus and tinnitus-associated distress (Lehtimäki et al 2013, Ylikoski et al 2017).
Mental stress is a huge problem in today’s society: about half of work-related illnesses are directly or indirectly related to stress. It affects several physiological processes in the human body. When a person is exposed to a stressor, the autonomic nervous
system (ANS) is triggered: the parasympathetic nervous system is suppressed and the sympathetic nervous system is activated. This process is known as the ‘fight-or-flight’ reaction with secretion of the stress hormones into the blood stream leading to, for example, vasoconstriction of blood vessels, increased blood pressure, increased muscle tension and a change in heart rate (HR) and heart rate variability (HRV). When the stressor is no longer present, a negative feedback system stops cortisol production in the body, and a sympathovagal balance is established through homeostasis between the parasympathetic (vagal) and sympathetic system.
The activity of the vagus nerve (VN) is responsible of the function of the parasympathetic nervous system. Its activity is considered to be associated with health and well being. Therefore, questions concerning the role of VN for therapeutic manipulation are emerging. Low vagal activity or responsiveness is associated with speciﬁc personality factors such as hostility, type A behavior (Type A: high-strung and Type B: the easy-going) and several medical risk factors. Furthermore, stressful events can promote a phasic decrease of HRV, and chronic stress leads to allostatic load accompanied by dampened vagal activity. In addition to these risk factors, evidence shows a link between low vagal activity and somatic or psychiatric morbidity and mortality, possibly mediated by associations between vagal activity and glucose regulation, HPA (hypothalamic–pituitary–adrenal) axis functioning and inﬂammatory processes. All these negative associations are paralleled by an augmenting interest in interventions targeting the VN.
Although scientists have long been interested in whether and how stimulation of cranial nerves might produce changes in higher cortex, it was not until the mid-1980s that electrical stimulation of the vagus nerve was developed as a potential therapy. In 1985, the ability of vagus nerve stimulation (VNS) to abort seizures was proven in canine studies (Zabara, 1992). A ﬁrst human implant of a VNS generator was developed and introduced in humans in 1988 for the treatment of therapy-resistant epilepsy (Penry and Dean,1990; Wheless et al., 2001)).
Vagus nerve stimulation (VNS) has become an established therapy for difficult-to-treat epilepsy during the past 25 years. The vagus nerve provides a unique entrance to the brain. Electrical stimulation of this structure in the cervical region allows direct modulative access to subcortical brain areas, requiring only minimally invasive surgery with low risks involved. VNS therapy has shown to reduce epileptic seizures both in number and severity in a group of patients not responding to antiepileptic drugs. The effects are accompanied by an atypical set of central side effects.
After the success of the VNS therapy with epilepsy, the technique has been applied to a wide variety of disorders, ranging from major depressive disorder to Alzheimer’s disease (Fig.1). The results of several of these are promising.
In conventional (=implanted) vagus nerve stimulation (VNS) therapy, a bipolar helical electrode is placed around the cervical vagal nerve (tenth cranial nerve) at the level of about the fifth to sixth cervical vertebra, which is stimulated in a regular cycle. These pulses are generated by a connected pulse generator placed in the chest wall (Beekwilder and Beems 2010) (Fig.2).
Central vagal pathways
Vagal aﬀerents traverse the brainstem in the solitary tract, with terminating synapses located mainly in the nuclei of the dorsal medullary complex of the vagus (Fig. 3). Among medullary structures, the nucleus of the tractus solitarius (NTS) receives the greatest number of vagal aﬀerent synapses. The NTS projects to a wide variety of structures within the posterior fossa including all of the other nuclei of the dorsal medullary complex, the parabrachial nucleus and other pontine nuclei, and the vermis and inferior portions of the cerebellar hemispheres (Henry, 2000). The parabrachial nucleus projects to several structures including the hypothalamus, the thalamus, the amygdala, the anterior insular, and infra-limbic cortex, lateral prefrontal cortex, and other cortical regions. Through its projection to the amygdala, the NTS gains access to amygdala-hippocampus-entorhinal cortex pathways of the limbic system. In addition, the NTS projects to the locus coeruleus, which provides widespread noradrenergic innervation of the entire cortex, and to raphe nuclei providing widespread serotonergic innervation of the brain (Henry, 2000).
Mechanism of VNS therapy
Although the exact mechanism through which VNS therapy displays its various effects is not known, many pieces of the puzzle have been found (Henry, 2002; Nemeroff et al., 2006). The antiepileptic effects have been attributed to several processes.
First, VNS causes an increased synaptic activity in the thalamus and thalamocortical projection pathways, which would result in an increased arousal and possibly a decreased synchrony of synaptic activities between and within cortical regions.
Second, VNS leads to intermittently increased synaptic activities in components of the central autonomic system, such as the insula and the hypothalamus.
Third, there is transiently decreased synaptic activity in components of the limbic system, such as the amygdala and the hippocampus.
And finally, VNS therapy results in intermittently increased release of norepinephrine and serotonin over widespread cerebral regions. All these regions are either innervated directly by the vagus or indirectly through the nucleus tractus solitarius (NTS). The fibers of the left vagus nerve project bilaterally to the NTS. The central role of the NTS in the antiepileptic effects of VNS is demonstrated by the experiments of Walker et al. (1999) in which a decrease in NTS activity, by means of an increase in “-aminobutyric acid or a decrease in glutamate, had an anticonvulsant effect. The locus coeruleus also has a key role, which is directly connected to the NTS, as was shown by Krahl et al. (1998). In rats, lesioning of this area prevented VNS to control seizures. Activation of the locus coeruleus inhibited the development of kindling-induced seizures (Jimenez-Rivera et al., 1987).
The efficacy, putative mechanisms and possible adverse effects of VNS stimulation on CNS have been studied by
1. Imaging (positron emission tomography, PET; functional magnetic resonance imaging, fMRI)
2. Electrophysiologically (EEG & MEG, electroencephalography & magnetic encephalography) and
3. Clinically in patients
fMRI can image the brain every 3 s (or faster), while a ﬂuorodeoxyglucose PET scan sums activity over 20–30 min. On the other hand, the fMRI method is limited by its sensitivity to vasoactive changes.
In a landmark paper (Henry et al., 1998) VNS was delivered at high levels (500 ms, 30 Hz, 30 s on, 5 min oﬀ, mean 0.5 mA) in 5 patients and low levels (130 ms, 1 Hz, 30 s on, 180 min oﬀ, mean 0.85 mA) in different ﬁve patients. The high stimulation group had signiﬁcant blood ﬂow increases in the rostral and dorsal medulla oblongata. In both groups, VNS caused increased activity in the right thalamus, right postcentral gyrus, and bilateral inferior cerebellum. VNS-induced blood ﬂow alterations were also observed bilaterally in the hypothalami, as well as the anterior insula. The high-stimulation group had signiﬁcant blood ﬂow increases in the bilateral orbitofrontal gyri, right entorhinal cortex, and right temporal pole, which did not occur in the low-stimulation group. Both groups had signiﬁcant bilateral decreases in the amygdala, hippocamus, and posterior cingulate gyrus
Conway et al: after 10 weeks of VNS blood flow was signiﬁcantly higher in the bilateral orbitofrontal gyrus, left amygdala and parahippocampal gyrus, bilateral thalamus, left insula, and right cingulate gyrus. Areas of decreased activity included the bilateral cerebellum and right fusiform gyrus. In direct and puzzling contrast to the ﬁndings in PET studies, where increased thalamic activity was found with VNS, several SPECT examinations in epilepsy showed that VNS was associated with relatively decreased thalamic activity (Vonck et al., 2000).
BOLD fMRI can reveal the exact location and level of the brain’s immediate response to VNS. In early fMRI studies of VNS in epilepsy VNS showed activation in both frontal lobes, contralateral post-central gyrus, temporal, angular, and supramarginal gyrus, and parietal, occipital, insular lobes, and the cingulate gyrus was deactivated (Chae et al 2004).
Later studies showed that VNS at diﬀerent frequencies likely had frequency and/or dose dependent modulatory eﬀects on other brain activities such as hearing a tone. Furthermore, it was shown that VNS increased BOLD signals in the prefrontal gyri, caudate nuclei, temporal and parietal lobes and the cerebellum, consistent with the prior MUSC studies (Chae et al 2004).
VNS therapy was introduced in humans in 1988 for the treatment of therapy-resistant epilepsy by Penry and Dean (1990). In the subsequent years, several clinical trials were set up to assess the efficacy, safety, and tolerance of VNS therapy.
In 1995, the VNS study group published a randomized controlled study in 114 patients, with predominantly intractable partial seizures, comparing two VNS paradigms (Vagus Nerve Stimulation Study Group, 1995). The paradigms were high (therapeutic) stimulus intensity versus low (nontherapeutic) intensity. The high-intensity group received 0.25 to 3 mA pulses at 20 to 50 Hz, with 500-micro s pulse width, 30 to 90 seconds “on” time and 5 to 10 minutes “off” time, compared with the low-intensity group, which received 0.25 to 2.75 mA pulses at 1 to 2 Hz, with 130-micro s pulse width, 30 seconds on time, and 60 to 180 minutes off time. During the last 12 weeks of treatment, the “high” group had a significantly greater reduction in seizure frequency compared with their baseline as well as to the “low” group. Thirty-one percent of patients receiving the high stimulation had a reduction of 50% or more in seizure frequency. All patients elected to continue treatment in the extension phase of the study.
In 1998, a similar setup was used involving 198 patients, with complex partial seizures, receiving either high or low stimulation for a period of 12 to 16 weeks (Handforth et al, 1998). Compared with low stimulation, high stimulation significantly reduced overall seizure frequency. The authors also report a reduced amount of partial-onset seizures involving alteration of awareness (complex partial with secondarily generalized convulsions). Furthermore, global assessments of well-being showed greater improvements in the high group. As a result of these clinical studies, VNS therapy was approved as a treatment for medically refractory epilepsy in Europe in 1994 and in the United States and Canada in 1997. The evidence supporting VNS for epilepsy as safe and effective was classified as class I in 1999 by the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology (Fisher and Handforth, 1999). Long-term data up to 12 years of VNS experience showed that the therapeutic effects of VNS lasted for longer periods (Uthman et al., 2004).
In addition to a reduction in seizure frequency, Tatum et al. (2001) found that seizure duration and postictal recovery improved as a result of VNS in 15 of 21 patients. Similar results were observed by McHugh et al. (2007), with 19 of 48 patients reporting improvement in ictal and/or postictal severity. Hence, therapeutic effects of VNS are underestimated if only seizure frequency is taken as an outcome measure. In addition, Tatum found a reduction in the number and dosage of antiepileptic drugs.
VNS in Pediatrics
At first, VNS therapy was meant for adults. However, many studies have been performed with adolescents and young children. In 1997, the effects up to 30 months of VNS therapy in 19 children with refractory epilepsy were described corresponding the results received in adults. The results of children younger than and older than 12 years were compared retrospectively by Murphy et al. (2003). No differences were found in the seizure control in these two age groups. More than 50% seizure reduction was achieved in 23 of the 50 and 16 of the 34 for the younger and older groups, respectively. In the group of young children, Zamponi et al. (2008) described six children (“3 years) with catastrophic epilepsy and status epilepticus. One patient had no significant seizure reduction after 17 months. The other five patients all had 40% reduction in seizures of which two had 75% reduction. Six patients with refractory multifocal epilepsy younger than 5 years were described by Blount et al. (2006). One patient had no change in seizure status, five improved with two being seizure free.
Depression and VNS
Depression is a mental disorder characterized by sadness, loss of interest in normal daily activities, feelings of dejection and hopelessness, and diminished ability to experience pleasure. Estimates are that worldwide 15% to 17% (World Health Organization International Consortium in Psychiatric Epidemiology, 2000) of the population will have a period of depression during their lifetime. The majority of the major depressive episodes can be treated pharmacologically satisfactorily. Roughly, 30% of the people with major depressive episodes are not responding to medication. Part of this group can be satisfactorily treated, although often temporary, with electroconvulsion therapy.
Mood changes apparently unrelated to seizure improvement were a clue that VNS may also have antidepressant effects. Furthermore, a number of anticonvulsant drugs, such as carbamazepine and valproate, have been successfully used as antidepressants. Finally, VNS resulted in altered neurotransmitter and metabolite concentrations. Concentrations of “-aminobutyric acid, glutamate, serotonin, and norepinephrine, which are involved in mood, showed to be affected by VNS (Ben-Menachem et al., 1995). Therefore, an open study by Harden et al. (2000) was performed on the effect of VNS on mood of patients with epilepsy. With several depression rating scales, patients were tested before and after 3 months of VNS. The patients started with scores associated with mild depression. After 3 months, a significant reduction in the scores was found. In the comparison group, consisting of patients on a stable antiepileptic drug regimen, no change in scores was found. No differences were found between responders and nonresponders with respect to the seizure reduction, indicating that the antidepressant effect could not be attributed to the antiepileptic effects of VNS.
Elger et al. (2000) conducted a study with 11 patients in a randomized control trial. Five patients received low-intensity stimulation and six patients received high intensity. On a stable antiepileptic drug regimen, a significant reduction in depressive symptoms was found after 3 and 6 months, which seemed independent of seizure attenuation because of VNS.
The durability of the effects was studied to find whether the clinical benefits would persist (Sackeim et al., 2007). The depression scores were determined up to 24 months showing a lasting effect of the VNS therapy. This effect was the same for both early responders (#50% reduction of depression score after 3 months of VNS therapy) and late responders (#50% reduction of depression score after 12 months of VNS therapy).
Recently, the results of an European uncontrolled multicenter study were published (Schlaepfer et al., 2008). Seventy-four patients with treatment-resistant depression received VNS therapy and were followed up for 12 months. After 3 months of VNS therapy, 37% of the patients had responded, which gradually increased to 53% after 12 months with a remission rate of 33%. The study design had been similar to the first reports of Rush et al. (2000) and Sackeim et al. (2001b). The results found by Schlaepfer et al. showed higher response rates. The authors contributed this difference to lower measures of baseline depressivity in the latter study.
Side Effects and Adverse Events of VNS
With more patients undergoing VNS therapy, more became known about the adverse events associated with the therapy. The side effects were first described by Ramsay et al. (1994). Ramsay et al. reported no serious adverse events in 114 patients. Common side effects associated with VNS were primarily limited to the periods in which the stimulator was actually delivering pulses. These were hoarseness, throat pain, and coughing. In addition to these statistically significant side effects, several events seemed to be VNS related. These included abdominal pain, nausea, shortness of breath, and chest pain.
The side effects collected from patients enrolled in five previous clinical trials were published by Morris and Mueller (1999). The most common adverse events after 1 year were hoarseness (28%) and paresthesias in throat-chin region (12%), after 2 years hoarseness (19%) and cough (5.9%), and after 3 years shortness of breathe (3.2%). In general, the side effects are well tolerated. Ben-Menachem (2001) concluded that VNS side effects are usually related to stimulation itself and often improve with time. Unwanted side effects are easy to control by reducing the stimulation intensity. It does not cause central nervous system side effects, such as tiredness, psychomotor slowing, irritation, and nervousness, common in antiepileptic drugs.
In addition, there are clinical reports (Ali et al 2004;L Tatum et al 1999; Asconape et al 1999; Ardesch et al 2007) suggesting that vagal activation can be antiarrhythmic. In fact, some reports demonstrate that acute intraoperative vagus nerve stimulation (the first lead test) may create ventricular asystole in patients. This type of complication has been described during VNS implantation surgeries with a frequency of one of 865 (Asconape et al 1999). Therefore, the extracorporeal cervical vagus nerve stimulation testing is recommended to be performed with continuous EKG monitoring intraoperatively. This precaution should be applied also to the first session of tVNS in patients.
Transcutaneous vagus nerve stimulation (tVNS)
It was recently demonstrated in the rat tinnitus model that tinnitus-related maladaptive neuronal plasticity (MNP) might be reversed by a combination of (implanted) VNS and sound stimulation (Engineer et al 2011). A clinical pilot study in tinnitus patients using implanted VNS paired with sound showed promising results as well (Vanneste et al 2012)
However, the methodology of VNS used in epilepsy and depression may not be realistic for the treatment of most patients with tinnitus, because it is an invasive and expensive procedure.
There exists an afferent sensory branch of the vagus nerve, the ramus auricularis nervi vagi, which innervates the outer ear canal and parts of the auricle (Fig.4). This auricular branch of the vagus nerve (ABVN), also called the Arnold´s nerve, projects centrally to the nucleus of the solitary tract in the brainstem (Nomura et al 1984). It was demonstrated by functional magnetic resonance imaging (fMRI) and EEG recordings that tVNS of ABVN activates the central vagal pathways similarly as implanted VNS (Kraus et al 2007; Dietrich et al 2008; Polak et al 2009). Therefore, the stimulation of ABVN might be an easy, noninvasive and low-cost method to be used for tinnitus patients to obtain the beneficial effects of vagal system activation. tVNS allows the stimulation of the vagus nerve without surgical procedure. Electrical impulses are targeted at the aurical (ear), at points where branches of the vagus nerve have cutaneous representation. Specifically the medial part of tragus and concha has been target for tVNS. To date, there have been conducted several pilot studies on the effectiveness of tVNS in epilepsy and pain.
We have developed our own tVNS device which also has been tested in patients, particularly in order to apply tVNS for the treatment of tinnitus (Fig.5). Our recent pilot study (Lehtimäki et al 2013, Ylikoski et al 2017) answered to two questions: Does tVNS have therapeutic effects on patients with tinnitus? and Does tVNS have effects on the acoustically evoked neuronal activity of the auditory cortex?
For the first aim, we tested the efficacy of tVNS plus tailored ST in a short-term therapeutic trial. Our short-term pilot study showed that a combination of tVNS and tailored ST seems to reduce the severity of subjective tinnitus sensation and the tinnitus-associated distress, which is often the major problem in tinnitus patients. It is also worth noting that no adverse effects were observed during tVNS performed in the current study.
For the second aim, we investigated the possible acute neuromodulative effects of tVNS on evoked auditory cortical responses as measured by MEG in eight individuals with tinnitus. Our MEG results demonstrated that the auditory cortical responses can be modulated by the application of tVNS, suggesting an access to the auditory system through the vagus nerve. Thus, tVNS plus ST may have the potential of reducing aberrant activity in the auditory pathways thought to be associated with tinnitus.
Safety of VNS and tVNS
The best indication of the safety of VNS are the approvals of this treatment method by FDA (1997) and EU (1994), first for epilepsy and then for depression. Also the over two decades long time follow-up time of the usage of implanted VNS has not showed any significant adverse effects. Also, the evidence of the long-time clinical use of VNS supported to claim VNS as a safe and effective therapy for epilepsy and classiﬁed it as Level I in 1999 by the American Academy of Neurology.
Similarly, the first tVNS device, ”Nemos”, received CE approval in 2010 and SaluStim device in 2013. CE marking is an indication that a medical device complies with essential health and safety. Apart from its non-invasive character, the potential lack of peripheral side-effects in tVNS might partly be due to left-side stimulation. Parasympathetic cardiac innervation is for the most part provided by the right vagus nerve (Henry 2002). Moreover, peripheral side-effects like bradycardia or apnoea are known to mainly occur at stimulation intensities high enough to activate nociceptive C-fibres (Woodbury and Woodbury 1990). Given the non-painful, pleasant nature of sensations during tVNS, it is assumed that nociceptive fibres are not excited. As tVNS shares the modes of CNS-actions of implanted VNS it seems justified to state that tVNS is at least as safe as implanted VNS. This statement can be further stressed after the study of Kreuzer et al (2012) demonstrating the practically non-existing serious effects of tVNS on cardiac activity.
Efficacy of tVNS
The indication of the efficacy of VNS are the approvals of this treatment method by FDA (1997) and EU (1994), first for epilepsy and then for depression by FDA (2005). The efficacy of tVNS is mainly based earlier studies on implanted VNS (randomized placebo controlled trials) indicating that 30% of epilepsy patients would have a greater than 50% reduction of seizures and about 50% of patients experience a 40% or greater reduction in seizure frequency and severity (Beekwilder and Beems 2010).
The first tVNS device, Nemos, has been the object of several studies in which its mechanisms and efficacy has been investigated for pain relief (Ellrich 2012; Busch et al 2012; Ellrich et al 2011) and for reduction of epileptic seizures (Stefan et al 2012). In this report the authors state that the tVNS stimulation is a safe and well-tolerated method for relatively long periods, and might be an alternative treatment option for patients with epilepsy.
Our own studies show that transcutaneous vagus nerve stimulation, if combined with sound therapy, reduces the severity of tinnitus and tinnitus-associated distress (Lehtimäki et al 2013; Ylikoski et al 2017).
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