Posted by Ponder on June 14, 2003, at 1:13:06
In reply to Re: VNS [full] study results to be released soon, posted by jrbecker on June 11, 2003, at 11:07:32
This article contains some interesting stuff on VNS and neuroanatomy, but skip on down to the last three paragraphs for some intriguing and, perhaps, promising info. Neuroimaging technology may allow identification of optimal settings for these stimulators, so even better results may be possible. The increasing, or,at least,lasting efficacy over time looks good, too.
Is Vagus Nerve Stimulation the Next Breakthrough for Treatment-Resistant Depression? Ziad Nahas.
Byline: Ziad Nahas, M.D.
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 (Foley and DuBois, 1937, as cited in George et al., 2000), but 80% of its fibers are afferent and carry information from the viscera back to the brain. The fibers first enter the midbrain at the nucleus tractus solitaris (NTS) level. From the midbrain, they either loop back out in a reflex arc, connect to the reticular activating system or reach the parabrachial nucleus and its connections to the NTS; raphe nucleus; locus ceruleus; the thalamus; and paralimbic, limbic and cortical regions. It is through this route that vagus nerve stimulation (VNS) modulates brain function. Yoga and deep breathing (primarily regulated by the 10th cranial nerve) are clearly associated with CNS effects. This neuroanatomy may be important in how VNS treats epilepsy and potentially treats depression.
Over the past century, researchers have demonstrated that peripheral modulation of the vagus showed changes in CNS neuronal activity (Chase et al., 1966; MacLean, 1990; Van Bockstaele et al., 1999). The contemporary history of VNS started in 1985, when Zabara (1992) demonstrated the anticonvulsant action of VNS on experimental seizures in dogs during and after the stimulation periods. These lasting beneficial effects meant that residual changes in neurotransmitters or perhaps a certain degree of neuronal plasticity occurred and proved useful in controlling the seizures beyond the immediate stimulation. These observations led to the development of the VNS Therapy System (previously named the Neuro-Cybernetic Prosthesis) and an expanding amount of research, first in different types of seizure disorders (Penry and Dean, 1990), and later in other neuropsychiatric conditions such as depression.
The VNS Therapy pulse generator is a pacemaker-like device 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 eight to 10 years, making VNS an advantageous long-term treatment modality with 100% 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 arrhythmias 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" and is without significant gastrointestinal or cardiac side effects (Schachter and Saper, 1998), based on studies in both children (Nagarajan et al., 2000) and adults (Schachter and Saper, 1998). 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 approximately 35% compared to baseline at one year and has been shown to increase to 43% after three years of therapy (Morris et al., 1999). Some patients (as many as 10% or more) can be controlled solely with VNS (without anticonvulsant medications), but the majority continues with concomitant, albeit more simplified, pharmacotherapy.
The next chapter 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). This, in addition to the known neuroanatomy of the vagus, the role of anticonvulsants in treating mood disorders (Post, 1990), a positron emission tomography study showing brain activity changes in limbic regions attributed to VNS (Henry et al., 1998) and studies showing that modulating the locus ceruleus neurotransmitters homeostasis played a crucial role in the VNS therapeutic effects (Walker et al., 1999), led to exploring VNS for treating depression.
The first implant for this indication was performed in 1998 by researchers from the Medical University of South Carolina, who led an initial short-term, open-label pilot study of VNS in 30 adult outpatients with treatment-resis-tant, severe, non-psychotic major depressive episodes. This study reported a 30.5% response rate after eight weeks of VNS therapy, with a 50% reduction in baseline on the 28-item Hamilton Rating Scale for Depression (HAM-D-28). In this medication-resistant group, there was a 15.3% complete remission rate (exit HAM-D-28 < 10) (Rush et al., 2000). In a larger (n=60) study of vagus nerve stimulation, 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 nine months of long-term VNS treatment and changes in psychotropic medications showed an improved response rate from 30.5% to 45%. The remission rate significantly increased to 29% at one year. This open-label study provided important evidence that VNS is both feasible and safe. 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 Europe and Canada, but it has not been approved for this indication by the U.S. Food and Drug Administration.
To overcome the limitations of these open design studies, a multisite, randomized, sham-controlled study was necessary. The logistics imposed by such design were unlike most pharmacological trials. Vagus nerve stimulation 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 applied equally to both active and placebo arms to maximize the integrity of the blind.
A total of 235 subjects with moderate-to-severe refractory depressive episodes were enrolled. They were held constant on their psychotropic medications one month prior to implant and for the duration of the 12-week acute initial phase. After this initial phase, placebo non-responders were crossed over to active stimulation. The initial report did not achieve a statistically significant difference in three-month response with active VNS (15%), compared to the sham group (10%). This may have been in part due to an underpowering of the study and a more severely ill enrolled cohort compared to that which had been originally designed for and expected. In addition, the average intensity of stimulation in this multicenter, double-blind study is less than the stimulation intensity generally seen in epilepsy or in the initial depression study.
As in epilepsy, the predictive factors for positive outcome or guidelines for stimulation parameters have not yet been worked out (Koo et al., 2001), but an effort is underway to maximally increase the intensity of stimulation in non-responders.
Despite the lack of statistical significance demonstrated in the acute period, 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 nine months, during which both pharmacological and parameter dosing changes have been made, a response rate increase of 44% has been observed. Data at one-year follow up for all 235 subjects are not yet available. Clinical observations suggested that some of the responders appear to have stayed in remission longer than with psychotropic medications alone. If this holds true, this will be a great departure from traditional antidepressant treatments (including electroconvulsive therapy).
The mechanisms of action of VNS are still unknown. Human cerebrospinal fluid (CSF) studies in epilepsy patients reveal an increase in 5-HIAA, homovanillic acid (HVA) and g-aminobutyric acid and a decrease in glutamate after three months of treatment (Ben-Menachem et al., 1995). Vagus nerve stimulation causes increases in HVA in depressed subjects, and the increase in CSF norepinephrine may predict a better response to treatment. Patients with high corticotrophin-releasing factor or low 5-HIAA had a poor response to the VNS antidepressant effect (Carpenter et al., 2002). Sleep studies show a normalization of electroencephalograph rhythm patterns (Armitage et al., 2002). Functional brain imaging studies demonstrate that VNS causes immediate and long-term changes in brain regions implicated in neuropsychiatric disorders with vagus innervations. These include the thalamus, cerebellum, orbitofrontal cortex, limbic system, hypothalamus and medulla (Henry et al., 1998; Henry et al., 1999).
At the Medical University of South Carolina, researchers have succeeded in performing blood-oxygen-level function magnetic resonance imaging (BOLD fMRI) studies in depressed patients implanted with VNS generators (Bohning et al., 2001; Lomarev et al., 2002). These results show that VNS activates many anterior para-limbic regions in a dose-dependent fashion that changes over time. It appears that 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., 2002). 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 perform 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 (Figure).
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 beneficial and cost-effective in the long term for patients with depression. Other VNS open trials are underway in anxiety disorders (posttraumatic stress disorder, panic disorder and obsessive-compulsive disorder), the early stages of Alzheimer's disease, rapid-cycling bipolar disorder and migraine headaches. In a related venue, sub-diaphragmatic bilateral VNS is being tested in morbid obesity as it may modulate satiety signals.
poster:Ponder
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