Depression, Depressionen

Vagus Nerve Stimulation

Other Areas of Potential Research or Clinical Promise with VNS

Work to date has established that VNS is an effective anticonvulsant. Recent work suggests that VNS may have antidepressant properties. The vagus nerve is an important route of information into the CNS. Several theories of the anxiety disorders posit either a faulty interpretation of peripheral information into the CNS or erratic availability of same (Gray 1982; James 1984; Watkins et al 1998). lt is conceivable that altering the flow of this information with VNS could have therapeutic potential in anxiety disorders (e.g., generalized anxiety disorder, panic disorder) or irritable bowel syndrome.

Similarly, the vagus contains information about hunger, satiety, and pain. Potential studies in the areas of treatment-resistant obesity, addictions, and pain syndromes are also theoretically justified. Moreover, the NTS sends fibers into the dorsal raphe and areas that are known to control levels of alertness. Thus, VNS might be considered as a potential treatment for some disorders of sleep or alertness like coma or narcolepsy. For example, a recent study in 10 epilepsy patients found that high-intensity, high-frequency VNS reduced total time in rapid eye movement sleep, and such sleep was less fragmented (Vaugh and D‘Cruz 1999). Therefore, in addition to advancing our understanding of the pathophysiology of various neuropsychiatric disorders. VNS may have other therapeutic applications, which are guided by the known anatomy of vagus connections.

A recent study by Clark and colleagues hints at the potential for VNS to be used to investigate brain circuits involved in memory and learning (Clark et al 1999). These researchers examined word-recognition memory in 10 patients enrolled in a clinical study of VNS for epilepsy. Vagus stimulation administered after learning and during memory consolidation caused intensity-dependent enhancement of word recognition relative to sham stimulation. Other work has shown that vagotomy attenuates the memory-enhancing properties of amphetamine.

Further Refinements in the Use of VNS

At present, the delivery of VNS involves a surgical procedure that includes exposure and manipulation of the carotid artery, as well as the cosmetic and other inconveniences of having a generator in the chest wall. As a consequence, the NCP System is typically used in those patients who have not responded to other therapies. In both epilepsy and depression, sorne patients will receive little to no benefit, despite having had surgery. The development of less invasive ways of delivering VNS or predicting which patientS will benefit would likely expand the clinical potential of VNS. Preliminary attempts at externally stimulating the vagus nerve via a transcranial magnetic stimulator have not been successful, in part due to the difficulty of finding a reliable indication of whether TMS has activated the vagus (H. Sackeim et al, unpublished data, April 1998). Another possibility might be to develop a temporary percutaneous method of stimulation.

Yet a different approach would be to identify the subset of patients who are most likely to benefit from VNS, by using functional neuroimaging or other measures. In this context, a recent PET study in adults with epilepsy found that increased blood flow in the right and left thalamus during the initial VNS stimulation correlated with decreased seizures over the next few weeks (Henry et al 1999). This finding suggests that one could use functional imaging, combined with VNS, to select patients most likely to benefit from this therapy.

Finally, VNS can be delivered at different amplitudes and frequencies and with different pulse widths, all at various duty cycles (ratio of “on“ time to “off‘ time). More basic work would advance this area through an understanding of how varying combinations of these parameters affect different brain regions or influence different neuropsychiatric conditions. lt seems logical to suggest that VNS delivered with parameters different from those commonly used for epilepsy might produce different CNS effects that would in turn broaden the clinical indications.

Conclusion

Vagus nerve stimulation, one of the newest methods to physically alter brain function, builds on a long history of investigation of the relationship of autonomic signals with limbic and cortical function. Vagus nerve stimulation is already established as a clinically useful anticonvulsant in patients with resistant epilepsy and may have promise as an antidepressant treatment. The known anatomic projections of the vagus nerve suggest that VNS might also have other neuropsychiatric applications. Further research is needed to clarify the mechanisms of action of VNS and the potential clinical utility of this intriguing new somatic portal into the CNS.

Several authors hold research contracts (MSG, HAS, AJR, LBM) or grants (MSG, AJR) from Cyberonics, the manufacturer of the NCP System, which delivers VNS. No author has a direct financial interest in Cyberonics (stocks, consulting boards, etc.), and there was no compensation for writing this article. NCP and VNS are trademarks of Cyberonics.

Dr. George thanks Dr. Paul MacLean for helpful discussions about the relationship of the autonomic nervous system and the limbic system, with particular attention to the role of the vagus nerve and the nucleus solitary tract. The authors thank Burke Barrett and Dr. William Duffell of Cyberonics for comments on this article.