Vagus Nerve Stimulation

The vagus nerve is classically described as the "wandering nerve." It sends signals from the central nervous system to control the peripheral cardiovascular, respiratory, and gastrointestinal systems. However 80 percent of its fibers are afferent, carrying information from the viscera back to the brain (Foley et al., 1937). The fibers first enter the midbrain at the nucleus tractus solitarius (NTS) level. From the midbrain, they either loop back out to the periphery in a reflex arc, connect to the reticular activating system, or reach the parabrachial nucleus (PB) and its connections to the NTS, raphe nucleus (RN), locus ceruleus (LC), the thalamus, paralimbic, limbic, and cortical regions. It is through this route that vagus nerve stimulation (VNS) modulates brain function. In this context it is noteworthy that yoga and deep breathing (primarily regulated by the 10th cranial nerve) are clearly associated with CNS effects (Loo et al., 1999). This neuroanatomy may be important in understanding how VNS treats epilepsy and potentially treats depression.

Over the past century, the peripheral modulation of the vagus showed changes in CNS neuronal activity (Maclean, 1990; Chase et al., 1966; Van Bockstaele et al., 1999). The contemporary history of VNS started in 1985, when Jake Zabara first experimented and later demonstrated the anticonvulsant action of VNS on experimental seizures in dogs during and after the stimulation periods (Zabara, 1992). These lasting beneficial effects meant that residual changes in neurotransmitters or perhaps a certain degree of neuronal plasticity was facilitated, which proved useful in controlling the seizures beyond the immediate stimulation. These observations led to the development of a NeuroCybernetic Prosthesis (NCP system) and an expanding amount of research, first in different types of seizure disorders (Penry et al., 1990) and later in other neuropsychiatry conditions such as depression (Rush et al., 2000).

The NCP is a pacemaker-like generator implanted in the anterior chest wall. It is linked to leads wrapped around the cervical portion of the left vagus nerve and is easily programmable with an external wand to deliver mild electrical stimulation at a preset intensity, duration, pulse width, and duty cycle. The battery life averages 8 to 10 years, making VNS an advantageous long-term treatment modality with 100 percent compliance. The most critical part of the one-hour-long implantation procedure is the dissection of the vagus nerve from the carotid artery. The surgical complications are more related to the risks of anesthesia than to rare infections or trauma to the vagus nerve and its branches. Vocal chord paralysis may occur if the recurrent laryngeal nerve is damaged. A few cases of arrythmias have been reported at the initial onset of the stimulation in the operating room without any long-term consequences. The American Academy of Neurology concluded that VNS for epilepsy is both "effective and safe" without significant gastrointestinal or cardiac side effects (Schachter et al., 1998a) based on studies in both children (Nagarajan et al., 2002) and adults (Schachter et al., 1998b). The most common side effect has been voice alteration or hoarseness, generally mild and related to the intensity of the output current. The mean overall decline of seizure frequency is about 25 to 30 percent, compared to baseline (Morris et al., 1999). Some patients (up to at least 10 percent) can be controlled solely with VNS with termination of all anticonvulsant medications, but the majority continues with concomitant pharmacotherapy, albeit often following a more simplified regimen.

The next phase of VNS therapy emerged when studies in epilepsy began to offer clinical and later prospective evidence that VNS improved mood independently from seizure control (Elger et al., 2000; Harden et al., 2000). Several additional factors led to the exploration of VNS for treating depression: the known neuroanatomy of the vagus, the role of anticonvulsants in treating mood disorders (Post, 1990), a positron emission tomography (PET) study by Henry et al. (1998) showing brain activity changes in limbic regions attributed to VNS, and studies showing that modulating the locus ceruleus neurotransmitters homeostasis played a crucial role in the therapeutic effects of this method (Walker et al., 1999). The first implant for this indication was performed in 1998, at the Medical University of South Carolina. This group of researchers joined by University of Texas Southwestern in Dallas, Columbia University in New York, and Baylor College of Medicine in Houston led an initial open-label pilot study of VNS in 60 adult outpatients with severe, nonpsychotic, treatment-resistant major depressive episode. This study reported a 30.5 percent response rate after 8 weeks of VNS therapy, with a 50 percent reduction in baseline HDRS 28-item. In this medication-resistant group, there was a 15.3 percent complete remission rate (exit HDRS28 <10) (Rush et al., 2000). A history of treatment resistance and the amount of concurrent antidepressant treatment during the acute VNS trial predicted a poorer VNS outcome (Sackeim et al., 2001). An open, naturalistic follow-up study (Marangell et al., 2002) with an additional 9 months of long-term VNS treatment and changes in psychotropic medications showed an improved response rate from 30.5 percent to 45 percent. The remission rate significantly increased to 29 percent at one year. This open-label study provided important evidence that VNS is both a feasible and safe procedure in depressed subjects. It revealed the antidepressant effect size needed to design larger double-blind pivotal studies. Based on these data, VNS has been approved as a treatment for depression in western Europe (except the United Kingdom) and in Canada but is still considered experimental by the U.S. FDA.

To overcome the limits of these open design studies, a multisite randomized, sham-controlled study was necessary. The logistics imposed by such design were unlike most pharmacological trials. VNS can cause voice alterations, which could give away the blind. Research teams were divided into blinded raters and unblinded programmers. At each site visit, subjects had to be seen by the programmer first, who would turn off the device before allowing the blinded rating group to interact with the subjects. These steps were quasi-choreographed and applied equally to both active and placebo phases to maximize the integrity of the blind. In sum, 235 subjects with moderate to severe refractory depressive episode were enrolled. They were held constant on their psychotropic medications 1 month prior to implant and for the duration of the initial acute phase. This initial phase was 12 weeks long, after which placebo nonresponders were crossed over to active stimulation. The initial report failed to show a statistically significant difference in 3 month response with active VNS (15 percent) compared to the sham group (10 percent). This may have been in part due to an underpowering of the study and a more severely ill enrolled cohort compared to what had been originally designed and expected. In addition, the average intensity of stimulation in this multicenter double-blind study is less than the one generally seen in epilepsy or initial depression study.

Like in epilepsy, the predictive factors for positive outcome or guidelines for stimulation parameters have not yet been established (Koo et al., 2001), but an effort is underway to maximally increase the intensity of stimulation in nonresponders. Despite the negative short-term results, the therapeutic role of VNS is still unfolding. As in the open study, a gradual and steady response is being noticed. By following the first 36 implanted subjects in an open-label fashion for an additional 9 months, where both pharmacological and parameter dosing changes have been made, their response rate has increased to 44 percent and appears to be sustained. Data at one year follow-up for all 235 subjects are not yet available. Clinical observations also suggest that some of the responders appear to stay in remission longer than they originally did with psychotropic medications alone. If this holds true, this will be a great departure from traditional antidepressant treatments (including ECT) and would greatly add to our knowledge of the pathophysiology of the illness.

The exact mechanisms of action of VNS are still unknown. Human cerebrospinal fluid (CSF) studies in epilepsy patients reveal an increase in 5-hydroxyindole acetic acid (5-HIAA), homovanillic acid (HVA) and GABA and a decrease in glutamate after 3 months of treatment (Ben-Menachem et al., 1995). VNS causes increases in HVA in depressed subjects and the increase in CSF norepinephrine may predict a better response to treatment. Patients with high corticotropin releasing factor (CRF) or low 5-HIAA did not show a strong antidepressant effect (Carpenter et al., 2002).

Sleep studies show a normalization of EEG rhythm patterns. Functional brain imaging studies demonstrate that VNS causes immediate and longer-term changes in brain regions with vagus innervations and implicated in neuropsychiatry disorders. These include the thalamus, cerebellum, orbitofrontal cortex, limbic system, hypothalamus, and medulla (Henry et al., 1998, 1999). Our group has succeeded in performing blood oxygen level dependent (BOLD) fMRI studies in depressed patients implanted with VNS generators (Bohning et al., 2001; Lomarev et al., 2002). The results show that VNS activates many anterior paralimbic regions, in a dose-dependent fashion, that changes over time. It appears as if the chronic stimulation dynamically and differentially modulates prefrontal/limbic circuitry. The net effect over 10 weeks of VNS treatment in depressed patients appears to be a gradual deactivation of the limbic regions (Nahas et al., 2002a). It is still unclear whether these changes are frequency or intensity dependent. Because of the ability to image the immediate effect of VNS on brain activity, the fMRI technique offers a unique opportunity to do sophisticated parametric studies and is likely to inform us about VNS dosing. Ultimately, VNS/fMRI may also be used to individually determine the best stimulation parameters to help a particular patient (Fig. 17.3).

Before its widespread use, and given the initial high cost of the implant and surgical procedure, efforts are underway to document whether VNS is both efficacious and cost effective in the long term for patients with depression. Other VNS open trials are underway in anxiety disorders (PTSD, panic disorder, and OCD), in the early stages of Alzheimer disease, rapid cycling bipolar disorder, and migraine headaches. In a related venue, subdiaphragmatic bilateral VNS is being tested in morbid obesity as it may modulate satiety signals.

Figure 17.3. Vagus nerve stimulation (VNS)-induced regional cerebral activity by functional magnetic resonance imaging (fMRI). Nine subjects with depression who, on average, had the device implanted for 10.1 months. Immediately before the scan, the patient's VNS device was reprogrammed to a 7 sec on, 108 sec off stimulation cycle. The VNS frequency setting was 20 Hz, the pulse width was 500 ms, and the current settings, which were kept at the patient's treatment level setting, ranged from 0.5 to 1.25 mA (mean 0.54). Data were acquired at rest, with the VNS device on for 7 sec, acute VNS, for only 7 sec activated many brain regions including the orbitofrontal and parieto-occipital cortex bilaterally, the left temporal cortex, the hypothalamus, and the left amygdala. See ftp site for color image.

Figure 17.3. Vagus nerve stimulation (VNS)-induced regional cerebral activity by functional magnetic resonance imaging (fMRI). Nine subjects with depression who, on average, had the device implanted for 10.1 months. Immediately before the scan, the patient's VNS device was reprogrammed to a 7 sec on, 108 sec off stimulation cycle. The VNS frequency setting was 20 Hz, the pulse width was 500 ms, and the current settings, which were kept at the patient's treatment level setting, ranged from 0.5 to 1.25 mA (mean 0.54). Data were acquired at rest, with the VNS device on for 7 sec, acute VNS, for only 7 sec activated many brain regions including the orbitofrontal and parieto-occipital cortex bilaterally, the left temporal cortex, the hypothalamus, and the left amygdala. See ftp site for color image.

Do Not Panic

Do Not Panic

This guide Don't Panic has tips and additional information on what you should do when you are experiencing an anxiety or panic attack. With so much going on in the world today with taking care of your family, working full time, dealing with office politics and other things, you could experience a serious meltdown. All of these things could at one point cause you to stress out and snap.

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