Since the vagus is a mixed nerve, VNS always comprises a portion of efferent stimulation which may alter peripheral functions. For instance, it may cause hoarseness as the most common adverse effect of VNS. As a matter of course, any changes concerning mood or epileptic seizures must be due to cerebral changes. However, from a theoretical point of view one has good reasons to expect that peripheral changes induced by efferent VNS may in turn result in cerebral changes relevant for the issues discussed here.
In mammalians the efferent branch of the vagus plays a decisive role in emotion regulation and expression (Porges 1997; Porges et al., 1994). Furthermore, the vagus is supposed to coordinate and protect the organism's metabolic resources, e.g. by retarding heart rate more or less ('vagal brake') (Porges, 1995). This more theoretical view is confirmed by clinical observations in neuropsychiatric disorders such as depression and anxiety which reveal clear associations between mood and parasympathetic functions (Glassman, 1998; Lehofer et al., 1997, 1999). Diurnal mood variations in some depressed patients may be associated with parasympa-thetic activity (Rechlin et al., 1995). Regarding cardiac measures, it is noteworthy that there is no evidence for altered vagal tone in unmedicated clinical depressions but for increased sympathetic tone (heart rate) which may be due to increased anxiety in depressed patients (Lehofer et al., 1997; Yeragani et al., 1991). Interestingly, experimentally induced panic attacks (hyperventilation, sodium lactate administration) are accompanied by an attenuated vagal tone (George et al., 1989) suggesting that anxiety disorders may be even more susceptible for VNS treatment than depressions. Other authors have also suggested a linkage between vagal functions and anxiety disorders (Watkins et al., 1998).
In animal experiments, one can transiently block efferent neural transmission by a lidocaine injection below the point of electrical stimulation (Brodin, 1985). In such an experiment, Clark et al. (1998) could show that effects on retention and recognition exclusively resulted from the afferent portion of VNS. Investigating the role of efferent vagal transmission in patients is difficult. One would have to record peripheral physiological measures and consider them as covariates during data analysis. Even if there is no evidence for general alterations of cardiac or gastrointestinal functions due to VNS in the sense of adverse effects (Ramsay et al., 1994), peripheral changes induced by VNS may be small and more difficult to register.
In the Elger et al. (2000) study, mood improvements were particularly expressed in a reduction of negative symptoms as recorded by the Scale for the Assessment of Negative Symptoms (Andreasen, 1981) or by the anergia scale of the Brief Psychiatric Rating Scale (Overall and Gorham, 1962). We propose that negative symptoms and particularly anergia may be interpreted as a lack of energy in which the autonomic nervous system and particularly the vagus may be involved.
Preliminary data of our on-going self-report questionnaire study suggest that VNS improves 'anxiety' and 'unpleasant exertion' as recorded by the Self-Rating Anxiety Scale (Zung, 1971) or the Befindlichkeits-Skala (Zerssen et al., 1970). In contrast, improvement of depressed mood, which was measured by the Beck Depression Inventory, appears to be a smaller effect. One has to consider that this self-report questionnaire particularly accounts for higher cognitive and emotional aspects of depression. Therefore, we assume that efferent VNS may contribute to mood improvements, first and more unspecifically, by tuning the basic autonomic balance and the vagal management of metabolic resources, or second and more specifically, by attenuating sympathetic tone and peripheral symptoms of anxiety.
Finally, we would like to allude to some theoretical difficulties associated with the fact that the vagus is more part of a 'system' than two 'one-way routes': VNS has an impact on the entire vagal brain-periphery feedback loop and electrical stimulation affects signalling in both directions. A vagus under VNS may make the brain 'think' that peripheral functions have changed - even if they actually have not, that is, even if no objective changes can be revealed by psychophysiological measurements. Such a mechanism could be described as virtually peripheral. Conversely, VNS may distort or suggest commands coming from the brain which are to be transmitted to the periphery by the vagus. This virtually cerebral mechanism results in peripheral effects, as for example hoarseness. Studies on the alterations of neural transmission within the vagus as induced by VNS would be required. So far, the artificial stimulation of the vagal system by VNS - with its unphysiological duty cycles, output currents and pulse frequencies - has to be regarded as very coarse. In fact, some authors assume that this is the true reason why more serious cardiac side effects do not occur in patients under VNS (George et al., 2000). A better understanding of vagal neurotransmission will provide the basis for more subtle, more adaptive and hopefully even more effective brain stimulation techniques in the future. VNS is probably the promising beginning of this intriguing development and an important scientific tool for human research on these issues.
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